Heterocyclic compounds

ABSTRACT

Pharmaceutically useful heterocyclic compounds, compositions containing them, and methods of using them, for example, as histamine H 3  receptor mediators.

FIELD OF THE INVENTION

[0001] The present invention relates to heterocyclic derivatives usefulin methods of treating neurologic and other disorders and conditionsmediated by the histamine H₃ receptor.

BACKGROUND OF THE INVENTION

[0002] Histamine [2-(imidazol-4-yl)ethylamine] is a transmittersubstance. Histamine exerts a physiological effect via multiple distinctG-protein coupled receptors. It plays a role in immediatehypersensitivity reactions and is released from mast cells followingantigen IgE antibody interaction. The actions of released histamine onthe vasculature and smooth muscle system account for the symptoms of theallergic response. These actions occur at the H₁ receptor (Ash, A. S. F.and Schild, H. O., Br. J. Pharmacol., 1966, 27, 427) and are blocked bythe classical antihistamines (e.g. diphenhydramine). Histamine is alsoan important regulator of gastric acid secretion through its action onparietal cells. These effects of histamine are mediated via the H₂receptor (Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R.and Parsons, E. M., Nature, 1972, 236, 385) and are blocked by H₂receptor antagonists (e.g. cimetidine). The third histamine receptor—H₃— was first described as a presynaptic autoreceptor in the centralnervous system (CNS) (Arrang, J. -M., Garbarg, M., and Schwartz, J. -C.,Nature 1983, 302, 832) controlling the synthesis and release ofhistamine. Recent evidence has emerged showing that the H₃ receptors arealso located presynaptically as heteroreceptors on serotonergic,noradrenergic, dopaminergic, cholinergic, and GABAergic(gamma-aminobutyric acid containing) neurons. These H₃ receptors havealso recently been identified in peripheral tissues such as vascularsmooth muscle. Consequently there are many potential therapeuticapplications for histamine H₃ agonists, antagonists, and inverseagonists. (See: “The Histamine H ₃ Receptor-A Target for New Drugs”,Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998; Morisset etal., Nature, 2000, 408, 860-864.) A fourth histamine receptor —H₄— wasrecently described by Oda et al., (J. Biol. Chem., 2000, 275,36781-36786).

[0003] The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin etal, Br. Res., 1990, 523, 325; Monti et al Eur. J. Pharmacol., 1991, 205,283). Their use in the treatment of migraine has also been suggested(McLeod et al Abstr. Society Neuroscience, 1996, 22, 2010) based ontheir ability to inhibit neurogenic inflammation. Other applicationscould be a protective role in myocardial ischemia and hypertension whereblockade of norepinephrine release is beneficial (Imamura et al J.Pharmacol. Expt. Ther., 1994, 271, 1259). It has been suggested thathistamine H₃ agonists may be beneficial in asthma due to their abilityto reduce non-adrenergic non-cholinergic (NANC) neurotransmission inairways and to reduce microvascular leakage (Ichinose et al Eur. J.Pharmacol., 1989,174, 49).

[0004] Several indications for histamine H₃ antagonists and inverseagonists have similarly been proposed based on animal pharmacologyexperiments with known histamine H₃ antagonists (e.g. thioperamide).These include, dementia, Alzheimer's disease (Panula et al Abstr.Society Neuroscience, 1995, 21, 1977), epilepsy (Yokoyama et al Eur. J.Pharmacol., 1993, 234, 129) narcolepsy, eating disorders (Machidori etal Brain Research 1992, 590, 180), motion sickness, vertigo, attentiondeficit hyperactivity disorders (ADHD), learning and memory (Barnes etal Abstr. Society Neuroscience, 1993, 19, 1813), schizophrenia(Schlicker et al Naunyn-Schmiedeberg's Arch. Pharmacol., 1996, 353,290-294); (also see; Stark et al Drugs of the Future, 1996, 21, 507 andLeurs et al Progress in Drug Research, 1995, 45, 107 and referencescited therein). Histamine H₃ antagonists, alone or in combination with ahistamine H₁ antagonist, are reported to be useful for the treatment ofupper airway allergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and5,869,479). Recently, a histamine H₃ antagonist (GT-2331) was identifiedand is being developed by Gliatech Inc. (Gliatech Inc. Press ReleaseNov. 5, 1998; Bioworld Today, Mar. 2, 1999) for the treatment of CNSdisorders.

[0005] As noted, the prior art related to histamine H₃ ligands wascomprehensively reviewed recently (“The Histamine H ₃ Receptor-A Targetfor New Drugs”, Leurs, R., and Timmerman, H., (Editors), Elsevier,1998). Within this reference the medicinal chemistry of histamine H₃agonists and antagonists was reviewed (see Krause et al and Phillips etal respectively). Thus the importance of an imidazole moiety containingonly a single substitution in the 4 position was noted together with thedeleterious effects of additional substitution on activity. Particularlymethylation of the imidazole ring at any of the remaining unsubstitutedpositions was reported to strongly decrease activity.

[0006] More recently several publications have described histamine H₃ligands that do not contain an imidazole moiety. For example; Ganellinet al Arch. Pharm. (Weinheim, Ger.) 1998, 331, 395; Walczynski et alArch. Pharm. (Weinheim, Ger.) 1999, 332, 389; Walczynski et al Farmaco1999, 684; Linney et al J. Med. Chem. 2000, 2362; Tozer and KalindjianExp. Opin. Ther. Patents 2000, 10,1045-1055; U.S. Pat. No. 5,352,707;PCT Application WO99/42458, Aug 26, 1999; and European PatentApplication 0978512, Feb 9, 2000.

[0007] We now describe a series of heterocyclic derivatives with theability to modulate the activity of the histamine receptor, specificallythe H₃ receptor.

SUMMARY OF THE INVENTION

[0008] The present invention provides compounds of the formula (I):

[0009] wherein:

[0010] Q¹ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl and C₂₋₇ alkenyl;

[0011] wherein Q¹ may be substituted with one or more substituentsselected from the group consisting of halo, cyano, hydroxy, OR¹¹, C₁₋₅alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino (H₂N—), R¹¹HN—,R¹¹R¹²N—, amido (H₂NC(O)), R¹¹HNC(O), R¹¹R¹²NC(O) and R¹¹OC(O), and

[0012] wherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅ haloalkylor C₂₋₅ alkenyl;

[0013] M is a moiety of the formula —CH₂R^(M), —CHOHR^(M), —C(═O)R^(M)or —C(═N—OH)R^(M),

[0014] wherein, R^(M) is selected from the group consisting of C₁₋₇alkyl, R^(M1)HN—, R^(M1)R^(M2)N—, cycloalkyl, aryl, biaryl andheterocyclyl,

[0015] wherein R^(M) may be substituted with one or more substituentsindependently selected from the group consisting of halo, cyano,hydroxy, OR^(M1), C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino(H₂N—), R^(M1)HN—, R^(M1)R^(M2)N—, amido (H₂NC(O)), R^(M1)HNC(O) andR^(M1)R^(M2)NC(O), and

[0016] wherein R^(M1) and R^(M2) are independently C₁₋₅ alkyl, C₁₋₅haloalkyl or C₂₋₅ alkenyl;

[0017] or M is hydrogen;

[0018] A³ is NH, NR³, sulfur, sulfoxide, sulfone or oxygen, wherein R³is C₁₋₅ alkyl;

[0019] L³ is C₁₋₇ alkyl or C₂₋₇ alkenyl;

[0020] wherein L³ may be substituted with one or more substituentsselected from the group consisting of halo, hydroxy, methoxy and amino(H₂N—);

[0021] or L³ is absent; and

[0022] Q³ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl, C₂₋₇ alkenyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl, aryl, 4-7membered heterocyclyl, (C₃₋₇cycloalkyl)-(4-7 membered heterocyclyl, 4-7membered heterocyclyl) —C₃₋₇ cycloalkyl, bi-(4-7 membered heterocyclyl),R³¹HN—, R³¹R³²N—, azinoyl (R³¹HN⁺(O⁻) or R³¹R³²N⁺(O⁻)),C₃₋₇cycloalkylamino, 4-7 membered heterocyclylamino, arylC₁₋₆alkylamino, C₃₋₇cycloalkylsulfanyl, 4-7 memberedheterocyclylsulfanyl and 4-7 membered heterocyclyloxy;

[0023] wherein Q³ may be substituted with one or more substituentsselected from the group consisting of halo, cyano, hydroxy, OR³¹, C₁₋₅alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino (H₂N—), R³¹HN—,R³¹R³²N—, amido (H₂NC(O)), R³¹HNC(O), R³¹R³²NC(O), R³¹OC(O),C₃₋₇cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7membered heterocyclyl C₁₋₆ alkyl, and

[0024] wherein R³¹ and R³² are independently C₁₋₅ alkyl, C₁₋₅ haloalkylor C₂₋₅ alkenyl;

[0025] or A³ and L³ are absent and Q³ is sulfanyl;

[0026] or a pharmaceutically acceptable ester, ether, N-oxide, amide,salt, hydrate or isotopically labeled form thereof.

[0027] The disclosed compounds, alone or in combination with a histamineH₁ receptor antagonist or a histamine H₂ receptor antagonist, are usefulfor treating or preventing neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma and allergic rhinitis ina subject in need thereof.

[0028] The present invention also provides process intermediates usefulin preparing compounds of Formula I. A preferred embodiment of thepresent invention is an intermediate compound of the formula (II):

[0029] wherein:

[0030] Q¹ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl and C₂₋₇ alkenyl;

[0031] wherein Q¹ may be substituted with one or more substituentsselected from the group consisting of halo, cyano, hydroxy, OR¹¹, C₁₋₅alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino (H₂N—), R¹¹HN—,R¹¹R¹²N—, amido (H₂NC(O)), R¹¹HNC(O), R¹¹R¹²NC(O) and R¹¹OC(O), and

[0032] wherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅ haloalkylor C₂₋₅ alkenyl;

[0033] R^(M) is selected from the group consisting of methyl, R^(M1)HN—,R^(M1)R^(M2)N—, C₅₋₇cycloalkyl (e.g., cyclopentyl or cyclohetyl), aryl,biaryl (e.g., haphthyl, or (4-phenyl) phenyl and 4-7 memberedheterocyclyl with between 0 and 2 heteroatoms,

[0034] wherein R^(M) may be substituted with one or more substituentsindependently selected from the group consisting of halo, cyano,hydroxy, OR^(M1), C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino(H₂N—), R^(M1)HN—, R^(M1)R^(M2)N—, amido (H₂NC(O)), R^(M1)HNC(O) andR^(M1)R^(M2)NC(O), and

[0035] wherein R^(M1) and R^(M2) are independently C₁₋₅ alkyl, C₁₋₅haloalkyl or C₂₋₅ alkenyl;

[0036] L³ is C₁₋₇ alkyl or C₂₋₇ alkenyl;

[0037] wherein L³ may be substituted with one or more substituentsselected from the group consisting of halo, hydroxy, methoxy and amino(H₂N—);

[0038] or L³ is absent; and

[0039] Q⁴ is hydrogen;

[0040] or a derivative thereof that bears one or more protecting groups.

DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention provides compounds of the formula (I):

[0042] and the formula (II):

[0043] described in the Summary section above. The invention encompassesthe described compounds or pharmaceutically acceptable esters, ethers,N-oxides, amides, salts, hydrates or isotopically labeled forms thereof.

[0044] A preferred embodiment of the present invention is a compound ofFormula I wherein Q¹ is unsubstituted or substituted C₁₋₇ alkyl, morepreferably unsubstituted or substituted C₁₋₅ alkyl, and most preferablyunsubstituted C₁₋₃ alkyl. Preferred substituents are those having abasic amine.

[0045] A preferred embodiment of the present invention is a compound ofFormula I wherein Q¹ is methyl.

[0046] Another preferred embodiment of the present invention is acompound of Formula I wherein M is a moiety of the formula —CH₂R^(M),—CHOHR^(M), —C(═O)R^(M) or —C(═N—OH)R^(M), and more preferably—CHOHR^(M), —C(═O)R^(M) or —C(═N—OH)R^(M).

[0047] Another preferred embodiment of the present invention is acompound of Formula I wherein R^(M) is unsubstituted or substitutedC₃₋₇cycloalkyl, aryl or 4-7 membered heterocyclyl.

[0048] Another preferred embodiment of the present invention is acompound of Formula I wherein R^(M) is aryl, and more preferably phenyl,unsubstituted or substituted with halo, cyano, hydroxy, methoxy, C₁₋₃alkyl, perhalomethyl, nitro or amino, and preferably substituted with F,Cl, Br, cyano, methoxy, C₁₋₃ alkyl, hydroxy, CF₃ or nitro.

[0049] Another preferred embodiment of the present invention is acompound of Formula I wherein A³ is oxygen, sulfur or NH, and morepreferably oxygen or sulfur, and most preferably oxygen.

[0050] Another preferred embodiment of the present invention is acompound of Formula I wherein L³ is unsubstituted or substituted C₁₋₅alkyl or C₂₋₅ alkenyl.

[0051] Another preferred embodiment of the present invention is acompound of Formula I wherein: L³ is selected from (a) C₁₋₃ alkyl, whichmay be unsubstituted or substituted, and independently may be unbranchedor branched, and (b) C₄₋₅ alkyl, which is branched or substituted, orboth. Examples of preferred L³ include methyl, ethyl, propyl,1-methylethyl (isopropyl), 1-methylpropyl, 2-methylpropyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl and 2-ethylpropyl.

[0052] Another preferred embodiment of the present invention is acompound of Formula I wherein L³ is absent.

[0053] Another preferred embodiment of the present invention is acompound of Formula I wherein Q³ is R³¹HN— or R³¹R³²N—, or anunsubstituted or substituted nitrogen-containing 5-6 memberedheterocyclyl, C₃₋₆ cycloalkyl-5-6 membered heterocyclyl, 5-6 memberedheterocyclyl —C₃₋₆ cycloalkyl or bi-heterocyclyl, and more preferablyR³¹R³²N— or an unsubstituted or substituted nitrogen-containing 5-6membered heterocyclyl.

[0054] Another preferred embodiment of the present invention is acompound of Formula I wherein: Q¹ is methyl; M is a moiety of theformula —CH₂R^(M), —CHOHR^(M), —C(═O)R^(M) or —C(═N—OH)R^(M); R^(M) isphenyl (or pyridinyl, or both) unsubstituted or substituted with F, Cl,Br, cyano, methoxy, C₁₋₃ alkyl, CF₃ or nitro; A³ is oxygen or sulfur; L³is selected from (a) C₁₋₃ alkyl, which may be unsubstituted orsubstituted, and independently may be unbranched or branched, and (b)C₄₋₅ alkyl, which is branched or substituted, or both; and Q³ isR³¹R³²N—.

[0055] Another preferred embodiment of the present invention is acompound of Formula I wherein: Q¹ is methyl; M is a moiety of theformula —CH₂R^(M), —CHOHR^(M) or —C(═O)R^(M); R^(M) is phenylunsubstituted or substituted with F, Cl, Br, cyano, methoxy, C₁₋₃ alkyl,CF₃ or nitro; A³ is oxygen or sulfur; L³ is unsubstituted or substitutedC₁₋₅ alkyl or C₂₋₅ alkenyl, or L³ is absent; and Q³ is an unsubstitutedor substituted nitrogen-containing 5-6 membered heterocyclyl (e.g.,piperidino, piperazino, or N-substituted 4-piperidinyl).

[0056] Another preferred embodiment of the present invention is acompound of formula I wherein:

[0057] Q¹ is C₁₋₃alkyl

[0058] wherein Q¹ may be substituted with one substituent selected fromthe group consisting of amino, R¹¹HN—, R¹¹R¹²N—, amido, R¹¹HNC(O),R¹¹R¹²NC(O) and R¹¹OC(O), and

[0059] wherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅ haloalkylor C₂₋₅ alkenyl;

[0060] M is a moiety of the formula —CH₂R^(M), —CHOHR^(M), or—C(═O)R^(M),

[0061] wherein, R^(M) is selected from the group consisting of C₁₋₃alkyl, R^(M1)HN—, C₁₃ R^(M1)R^(M2)N—, C₅₋₇cycloalkyl, aryl, biaryl and4-7 membered heterocyclyl containing between 1 and 2 heteroatoms,

[0062] wherein R^(M) may be substituted with one or more substituentsindependently selected from the group consisting of halo, cyano,hydroxy, OR^(M1), C₁₋₅ alkyl, nitro, and amino; and

[0063] A³ is sulfur or oxygen

[0064] L³ is C₁₋₇ alkyl or C₂₋₇ alkenyl;

[0065] wherein L³ may be substituted with one or more substituentsselected from the group consisting of halo, hydroxy, methoxy and amino(H₂N—);

[0066] or L³ is absent; and

[0067] Q³ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl, C₂₋₇ alkenyl, C₃₋₇cycloalkyl, C₁₋₇cycloalkenyl, aryl, 4-7membered heterocyclyl, C₃₋₇ cycloalkyl-4-7 membered heterocyclyl, 4-7membered heterocyclyl-C₃₋₇ cycloalkyl, bi-(4-7 membered heterocyclyl),R³¹HN—, R³¹R³²N—, azinoyl, C₃₋₇cycloalkylamino, 4-7 memberedheterocyclylamino, aryl C₁₋₆alkylamino, C₃₋₇cycloalkylsulfanyl, 4-7membered heterocyclylsulfanyl and 4-7 membered heterocyclyloxy;

[0068] wherein Q³ may be substituted with one or more substituentsselected from the group consisting of halo, cyano, hydroxy, OR³′, C₁₋₅alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino, R³¹HN—, R³¹R³²N—,amido, R³¹HNC(O), R³¹R³²NC(O), R³¹OC(O), C₃₋₇ cycloalkyl, monocyclic 4-7membered heterocyclyl and monocyclic 4-7 membered heterocyclylalkyl, and

[0069] wherein R³¹ and R³² are independently C₁₋₅ alkyl, C₁₋₅ haloalkylor C₂₋₅ alkenyl;

[0070] or A³ and L³ are absent and Q³ is sulfanyl;

[0071] or a pharmaceutically acceptable ester, ether, N-oxide, amide,salt, hydrate or isotopically labeled form thereof.

[0072] Preferred compounds of the present invention are as described inExamples I through V and XI through XVI.

[0073] More preferred compounds of the present invention are:

[0074](2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0075](4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;

[0076](4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;

[0077](4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0078](3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0079](4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;

[0080](4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;

[0081](4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanoneoxime;

[0082](4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0083][2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;

[0084](3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0085][2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;

[0086][2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitrophenyl)-methanone;

[0087](4-Bromophenyl)-[2-(11-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0088](4-Bromophenyl)-[2-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;

[0089](4-Chlorophenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylsulfanyl)-3H-imidazol-4-yl]-methanone;

[0090](4-Bromophenyl)-[3-methyl-2-(3-piperidin-4-yl-propylsulfanyl)-3H-imidazol-4-ylmethanone;

[0091] 4-{Hydroxy-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methyl}-benzonitrile; and

[0092](4-Bromophenyl)-[2-(1-sec-butyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone.

[0093] The present invention provides methods for the treatment ofdisorders and conditions modulated by a histamine receptor, moreparticularly the H₃ receptor, each method comprising administering adisclosed heterocyclic derivative.

[0094] Illustrative of the invention is a pharmaceutical composition forthe treatment of disorders mediated by the histamine H₃ receptor,comprising a pharmaceutically acceptable carrier and a disclosedcompound. The invention also provides a process for making apharmaceutical composition comprising formulating any of the compoundsdescribed herein and a pharmaceutically acceptable carrier.

[0095] Exemplifying the invention are methods of treating neurologicdisorders including sleep wake disturbances, attention deficithyperactivity disorders and cognitive dysfunction in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of any of the compounds or pharmaceutical compositionsdescribed herein.

[0096] An example of the invention is a method for treatment of sleepwake disturbances, attention deficit hyperactivity disorders andcognitive dysfunction in a subject in need thereof, comprisingadministering to the subject an effective amount of any of the compoundsor pharmaceutical compositions described herein.

[0097] Further illustrating the invention is a method of treating one ormore conditions selected from the group consisting of sleep/wake andarousal/vigilance disorders, migraine, neurogenic inflammation, asthma,dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease,epilepsy, narcolepsy, eating disorders, obesity, motion sickness,vertigo, attention deficit hyperactivity disorders, learning and memorydisorders, schizophrenia, upper airway allergic response, allergicrhinitis, substance abuse, bipolar disorders, manic disorders anddepression in a subject in need thereof, said method comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described herein.

[0098] Further exemplifying the invention is a method of producingimproved alertness or cognition in a subject in need thereof, comprisingadministering to the subject an effective amount of any of the compoundsor pharmaceutical compositions described herein.

[0099] For use in medicine, the salts of the compounds of this inventionrefer to non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts, which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali salts, for example, sodium or potassiumsalts; alkaline earth salts, for example, calcium or magnesium salts;and salts formed with suitable organic ligands, for example, quaternaryammonium salts. Representative pharmaceutically acceptable salts includethe following:

[0100] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

[0101] The present invention also provides prodrugs of the compounds ofthis invention. As used herein, “prodrugs” refer to compounds that arereadily convertible in vivo into a compound of Formula I. Thus in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various disorders described withthe compound specifically disclosed or with a compound that may not bespecifically disclosed, but that converts to the specified compound invivo after administration to the subject. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs”, ed. H. Bundgaard,Elsevier, 1985.

[0102] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. It is also understood that certain compounds of the presentinvention may possess structural arrangements that permit the structureto exist as tautomers, and as such, these tautomers are intended to beincluded in the present invention. Furthermore, some of the crystallineforms for the compounds may exist as polymorphs and as such are intendedto be included in the present invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents, and such solvates are also intended to be encompassedwithin the scope of this invention.

[0103] As used herein, “halo” or “halogen” shall mean chlorine, bromine,fluorine and iodine.

[0104] As used herein, the term “alkyl”, whether used alone or as partof a substituent group, shall include unbranched and branched carbonchains, preferably of one to seven carbon atoms and more preferably ofone to five carbon atoms, or one to three carbons, that are mono- ordi-valent. For example, where an alkyl group has one carbon atom, theterm “methyl” is used, which connotes the functional group (—CH₃), or(—CH₂—), as is chemically appropriate for a given substitution. Alkylgroups include but are not limited to methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like.

[0105] As used herein, the term “haloalkyl” shall denote unbranched orbranched, mono- or di-valent “alkyl” groups substituted with one or more“halo” atoms, preferably one to five “halo” atoms, more preferably oneto three “halo” atoms. “Haloalkyl” groups shall include partially andfully halogenated groups and groups with mixed halogens such as—CHCl—CH₂Cl, —CF₃, —CFCl₂, —CH(CH₂Br)—(CH₂)₃—CH₂₁ and—CCl₂—CH(CHCl₂)—CHCl—.

[0106] As used herein, the term “alkenyl”, whether used alone or as partof a substituent group, shall include unbranched and branched carbonchains, preferably of two to seven carbon atoms and more preferably oftwo to five carbon atoms, that are mono- or di-valent. For example,alkenyl groups include vinyl, ethylidine (for example, ethan-1-ylideneand ethan-1-yl-2-ylidene), allyl, pent-3-enyl, pent[3]eno,3-methylhex-4-enyl, and the like.

[0107] As used herein, unless otherwise noted, “alkoxy” shall denote thefunctional group (R—O⁻), where R is a mono-valent straight or branchedchain “alkyl” group as described above. For example, methoxy, ethoxy,n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy, and the like.

[0108] As used herein, unless otherwise noted, “cycloalkyl” shall denotea three- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cylcobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0109] As used herein, unless otherwise noted, “cycloalkenyl” shalldenote a three- to eight-membered, partially unsaturated, monocyclic,carbocyclic ring structure (preferably a five- to eight-membered,partially unsaturated, monocyclic, carbocyclic ring structure), whereinthe ring structure contains at least one double bond. Suitable examplesinclude cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,cyclohexa-1,3-dienyl, and the like.

[0110] As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, (4-phenyl) phenyland the like.

[0111] As used herein, unless otherwise noted, “arylalkyl” shall meanany “alkyl” group substituted with an aryl group such as phenyl,naphthyl, and the like, wherein the arylalkyl group is bound through thealkyl portion. Examples of an arylalkyl are benzyl, phenethyl, andnapthylmethyl.

[0112] As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any three- toeight-membered (preferably four- to seven-membered, and more preferablyfour- to six-membered) monocyclic, seven- to eleven-membered (preferablyeight- to ten-membered) bicyclic, or eleven- to fourteen-memberedtricyclic ring structure containing at least one (e.g., between 1 and 2,or between 1 and 3) heteroatom selected from the group consisting of N,O and S, optionally containing one to four (e.g., between 1 and 2, orbetween 1 and 3) additional heteroatoms, wherein the ring structure issaturated, partially unsaturated, aromatic or partially aromatic.Attachment through any heteroatom or carbon atom of the heterocyclylgroup that results in the creation of a stable structure is includedwithin this term.

[0113] Exemplary monocyclic heterocyclyl groups can include azetidinyl,thietanyl, pyrrolidyl, pyrrolyl, imidazolinyl, imidazolyl, triazolyl(such as 1H-[1,2,4]triazolyl and5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl), tetrazolyl, furyl, thienyl,oxazolyl, oxadiazolyl, thiazaolyl, thiadiazolyl, piperidyl, pyridyl,didehydropiperidyl, N-oxo-pyridyl, piperazyl, pyrimidyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepinyl, diazepanyl,and the like.

[0114] Exemplary bicyclic heterocyclyl groups can include thienofuryl,pyrrolopyridyl, furopyridyl, thienopyridyl, indolinyl, indolyl,indolizinyl, indazolyl, tetrahydroindazolyl, benzimidazolyl, purinyl,naphthyridinyl, quinolinyl, isoquinolinyl, quinuclidinyl,3,4-dihydro-4-oxoquinazolinyl, and the like.

[0115] Exemplary tricyclic heterocylclyl groups can include carbozolyl,acridyl, phenazyl, phenoxazyl, phenothiazinyl, thianthrenyl, and thelike.

[0116] As used herein, unless otherwise noted, “heterocyclylalkyl” shallmean any “alkyl” group substituted with a heterocyclyl group such aspiperidyl or pyridyl, and the like, wherein the heterocyclylalkyl groupis bound to the rest of the molecule through the alkyl portion.

[0117] As used herein, unless otherwise noted, the terms“cycloalkyl-heterocyclyl”, “heterocyclyl-cycloalkyl”, “bi-heterocyclyl”and “biaryl” shall denote independently selected pairs of cyclic systemsdirectly joined to each other by a single bond.

[0118] As used herein, unless otherwise noted, the terms“cycloalkylamino”, “heterocyclylamino”, and “arylalkylamino” shalldenote a secondary amino group substituted with cycloalkyl,heterocyclyl, and arylalkyl groups, respectively, wherein thecycloalkylamino, heterocyclylamino, and arylalkylamino substituents arebound through the amino nitrogen. Suitable examples of such substituentgroups include, but are not limited to, cyclohexylamino,piperidin-4-ylamino, benzylamino, and the like.

[0119] When a particular group is “substituted” (e.g., substitutedalkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or heterocyclyl-alkyl),that group may have one or more substituents, preferably from one tofive substituents, more preferably from one to three substituents, mostpreferably from one to two substituents, independently selected from thelist of substituents. Unless otherwise specified, the substituents areindependently selected from halo, cyano, C₁₋₅ alkyl, trifluoromethyl,hydroxy, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino, nitro,aryl, arylalkyl, and the like.

[0120] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[0121] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula:

[0122] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0123] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent, alone or incombination with another agent according to the particular aspect of theinvention, that elicits the biological or medicinal response in a tissuesystem, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includesalleviation of the symptoms of the disease or disorder being treated.For example, a method of treatment relating to a disclosed compound andanother compound specified in the claim can include (a) an independentlytherapeutically effective amount of the disclosed compound and anindependently therapeutically effective amount of the specifiedcompound; (b) an independently sub-therapeutically effective amount of adisclosed compound and an independently sub-therapeutically effectiveamount of the specified compound; or (c) an independentlytherapeutically effective amount of one compound and an independentlysub-therapeutically effective amount of the other compound. Theinvention features any of the above combinations such that theco-administration steps, the co-administration amounts, or both thesteps and the amounts together provide the desired pharmaceuticaleffect. Advantages of such co-administration can include improvement inthe side-effect profiles of one or more of the co-administered agents.

[0124] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product that results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

[0125] Abbreviations used in the specification, particularly the Schemesand Examples, are as follows: Ac₂O acetic anhydride AcOH acetic acidt-BOC Tert-butyloxycarbonyl n-BuLi n-butyl lithium t-BuLi tert-butyllithium BuOH n- or 1-butanol mCPBA meta- or 3-chloroperoxybenzoic acidDME I ,2-dimethoxyethane DMF N,N-dimethylformamide DMSODimethylsulfoxide Et₃N Triethylamine Et₂O diethyl ether EtOH EthanolKOt-Bu Potassium tert-butoxide LDA Lithium diisopropylamide LHMDSLithium bis(trimethylsilyl)amide LTMP Lithium tetramethylpiperidideMeNH₂ Methylamine MeOH Methanol NaBH(OAc)₃ Sodium triacetoxyborohydrideNaOEt sodium ethoxide NaOMe Sodium methoxide PCC Pyridiniumchlorochromate PDC Pyridinium dichromate (Ph₃P)₄Pdtetrakis(triphenylphosphine)palladium(0) PhSSPh Diphenyldisulfide RTroom temperature TFA Trifluoroacetic acid THF Tetrahydrofuran

[0126] The compounds of the present invention can be prepared by thefollowing reaction schemes. The starting materials and reagents used inthe following schemes are commercially available from such specialtychemical vendors, as Aldrich Chemicals Co., Fluka Chemical Corporation,and the like, or alternatively can be readily prepared by one ofordinary skill in the art. In those cases where a compound can beprepared by more than one reaction scheme of the present invention, thechoice of scheme is a matter of discretion that is within thecapabilities of one of ordinary skill in the art.

[0127] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0128] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in “Protective Groups in Organic Chemistry”, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 3^(rd) edition, John Wiley &Sons, 1999. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

[0129] Schemes for Synthesizing Compounds of Formula I

[0130] This disclosure includes Schemes I, II, III, VII, VIII, IX, X, XIand XII.

[0131] Following Scheme I above, compounds of Formula I of the presentinvention where M is —C(═O)R^(M), A³ is sulfur, and Q¹, R^(M), L³ and Q³are optionally varied, are prepared.

[0132] In Scheme I, optionally substituted compound 1 is treated firstwith a base, preferably an organometallic base (e.g. n-BuLi, LTMP, LDA,LHMDS or, more preferably, t-BuLi), at a low-temperature gradient(preferably from −78° C. to 0° C.) in a solvent such as diethyl ether,benzene, DME or, preferably, THF, and is then treated with aidehydeR^(M)CHO at low temperature (preferably −78° C.) to yield compound 2.Compound 2 is then treated with halide X-L³—Q³, where X is preferablychlorine, in the presence of a base (e.g. NaH, KOH or, preferably, K₂CO₃in acetone) to provide compound 3. Compound 3 is treated with anoxidizing agent (e.g. KMnO₄, PCC, PDC, “Swern” oxidation reagents suchas (COCl)₂/DMSO/Et₃N, or, preferably, MnO₂ in CH₂Cl₂) to yield thedesired compound 5 of the present invention. Alternatively, compound 2may be treated with Br—L³—Cl in the presence of a base (e.g. NaH, KOHor, preferably, K₂CO₃ in acetone) to provide compound 4. Compound 4 maybe treated with an oxidizing agent, preferably MnO₂ in CH₂Cl₂, to yieldcompound 6, which is then treated with primary or secondary amine Q³-Hin the presence of a base (e.g. K₂CO₃/acetone) to yield the desiredcompound 5 of the present invention. Alternatively, compound 4 may betreated with primary or secondary amine Q₃—H in the presence of a base(e.g. K₂CO₃/acetone) to provide compound 3, which is then treated withan oxidizing agent, preferably MnO₂ in CH₂Cl₂, to again yield thedesired compound 5 of the present invention.

[0133] Following Scheme II above, compounds of Formula I of the presentinvention, where Q¹ is methyl, M is —C(═O)R^(M), A³ is sulfur, andR^(M), L³, and Q³ are optionally varied, are prepared.

[0134] In Scheme II, alpha-bromoketone 7 is treated with methylamine indiethyl ether, followed by a solution of formyl acetic anhydride(preformed from the reaction of acetic anhydride and formic acid) toafford compound 8. Compound 8 is treated with ethyl formate and analkoxide (e.g. sodium methoxide, sodium tert-butoxide or, preferably,sodium ethoxide) in a solvent such as benzene or, preferably, THF, thencooled and treated with hydrochloric acid (10%) and potassiumthiocyanate to give compound 9. (See R. G. Jones, J. Am. Chem. Soc. 71,1949, 644.) Compound 9 is then treated with halide X-L³—Q³, where X ispreferably chlorine, in the presence of a base (e.g. NaH, KOH or,preferably, Cs₂CO₃) to provide the desired compound 5a of the presentinvention.

[0135] Following Scheme III above, compounds of Formula I of the presentinvention, where M is —C(═O)R^(M), A³ is NH, NR³, oxygen or sulfur, andQ¹, R^(M), L³ and Q³ are optionally varied are prepared. The startingmaterial (5b) is prepared using Scheme I. The L³ of the reagentH—A³—L³—Q³ is independent of L³ of formula 5b and formula 10 (both inSchme III).

[0136] In Scheme III, compound 5b (in which Q⁴ is hydrogen) is treatedwith an oxidizing agent, preferably hydrogen peroxide in acetic acid or3-chloroperoxybenzoic acid in dichloromethane or diethyl ether, toprovide compound 10. Desired compound 11 of the present invention isobtained upon treatment of compound 10 with H—A³—L³—Q³ in the presenceof a base (e.g. KH or, preferably, NaH) in a solvent such as DMF,benzene, DME or, preferably, THF.

[0137] Following Scheme VII above, compounds of Formula I of the presentinvention, where M is —CH₂R^(M), Q¹ is methyl, A³ is sulfur or oxygen,and R^(M), L³ and Q³ are optionally varied, are prepared. The startingmaterial (25) can be prepared using Schemes I, III, IX or X.

[0138] Desired compound 26 of the present invention is obtained uponreduction of compound 25 under “Wolff-Kishner” conditions, that is,treatment with hydrazine in the presence of a base (e.g. KOH, NaOH or,preferably, KOt-Bu) in a solvent such as ethylene glycol or, preferably,butanol at elevated temperature (e.g. 100° C.).

[0139] Following Scheme VIII above, compounds of Formula I of thepresent invention, where M is —C(═N—OH)R^(M), Q¹ is methyl, A³ is sulfuror oxygen, and L³, Q³ and R^(M) are optionally varied, are prepared. Thestarting material (25) can be prepared using Schemes I, III, IX or X.

[0140] Compound 25 is treated with hydroxylamine hydrochloride in thepresence of NaOAc or, preferably, pyridine in an alcoholic solvent (e.g.methanol or, preferably, ethanol) at elevated temperature (e.g. 80° C.)to afford the desired oxime compound 27 of the present invention.

[0141] Following Scheme IX above, compounds of Formula I of the presentinvention, where M is —C(═O)R^(M), Q¹ is methyl, and A³, L³, Q³ andR^(M) are optionally varied, are prepared.

[0142] Compound 20 is treated with an organolithium base (e.g. LDA,t-BuLi or, preferably, n-BuLi) at low temperature (preferably −78° C.)in a solvent such as DME, diethyl ether or, preferably, THF, followed bytreatment with an organodisulfide, preferably diphenyldisulfide, toafford compound 28. Compound 29 is obtained by treating compound 28 witha base (e.g. LHMDS, LDA or, preferably, LTMP) at low temperature(preferably −78° C.) in a solvent such as THF, followed by aldehydeR^(M)CHO. Compound 29 is treated with an oxidizing agent (e.g. KMnO₄,PCC, PDC, “Swern” oxidation reagents such as (COCl)₂/DMSO/Et₃N or,preferably, MnO₂ in CH₂Cl₂) to yield compound 30, which is treated withan oxidizing agent (e.g. hydrogen peroxide in acetic acid,3-chloroperoxybenzoic acid in dichloromethane, or, preferably,3-chloroperoxybenzoic acid in diethyl ether) to provide compound 31.Desired compound 25 of the present invention is obtained upon treatmentof compound 31 with H—A³—L³—Q³ in the presence of a base (e.g. KH or,preferably, NaH) in a solvent such as DMF, benzene, DME or, preferably,THF.

[0143] Following Scheme X above, compounds of Formula I of the presentinvention, where M is —C(═O)R^(M), Q¹ is methyl, and A³, L³, Q³, andR^(M) are optionally varied, are prepared. The starting material iscompound 28 from Scheme IX.

[0144] Compound 28 is treated with an oxidizing agent (e.g. hydrogenperoxide in acetic acid or, preferably, 3-chloroperoxybenzoic acid indiethyl ether) to provide compound 32. Compound 33 is obtained upontreatment of compound 32 with H—A³—L³—Q³ in the presence of a base (e.g.KH or, preferably, NaH) in a solvent such as DMF, benzene, DME or,preferably, THF. Compound 34 is obtained by treating compound 33 with abase (e.g. LHMDS, LDA or, preferably, LTMP) at low temperature(preferably −78° C.) in a solvent such as THF, followed by aldehydeR^(M)CHO. Compound 34 is treated with an oxidizing agent (e.g. KMnO₄,PCC, PDC, “Swern” oxidation reagents such as (COCl)₂/DMSO/Et₃N or,preferably, MnO₂ in CH₂Cl₂) to yield the desired compound 25 of thepresent invention.

[0145] Following Scheme XI above, compounds of Formula I of the presentinvention, where M is —C(═O)R^(M), Q¹ is methyl, A³ is sulfur, sulfoxideor sulfone, L³ is n-propyl, Q³ is dimethylamino or dimethylazinoyl andR^(M) is optionally varied, are prepared. In general, the startingmaterial (35), is prepared using Scheme X to provide appropriatelysubstituted 25 (i.e. compound 35). Where R^(M) is hydrogen, compound 35is obtained directly from 33 in Scheme X by treatment of the latterwith 1) LTMP and 2) DMF. Starting material may also be prepared usingSchemes I or III.

[0146] Compound 35 is treated with hydrogen peroxide in acetic acid toprovide desired compounds 36 of the present invention as a mixture ofdesired oxidation states. The product mixture is separated bychromatography (e.g. flash chromatography on silica gel).

[0147] Following Scheme XII above, compounds of Formula I of the presentinvention, where M is CH₂R^(M), R^(M) is optionally substituted —NR′R″(where R′ and R″ are independently C₁₋₇ alkyl or, taken together withthe nitrogen to which they are attached, form a four- to seven-memberednitrogen heterocycle), Q¹ is methyl, A³ is oxygen, L³ is n-propyl and Q³is N-piperidyl, are prepared. The starting material, compound 37, isprepared using Scheme X to provide appropriately substituted 33 (i.e. A³is oxygen, L³ is n-propyl and Q³ is N-piperidyl). Compound 37 is thenobtained directly from 33 in Scheme X by treatment of the latter with 1)LTMP and 2) DMF.

[0148] Desired compound 38 of the present invention is obtained bytreating compound 37 with an amine in the presence of a reducing agentsuch as NaBH₃CN or, preferably, NaBH(OAc)₃ in a solvent such asmethanol, ethanol, CF₃CH₂OH or, preferably, 1,2-dichloroethane.

[0149] The present invention provides a series of heterocyclicderivatives with the ability to modulate the activity of a histaminereceptor, specifically the H₃ receptor. These heterocycles includeN(1)-substituted imidazoles that contain both 2- and 5- substituents.

[0150] A number of compounds of the present invention that aremethylated at the N(1) position of the imidazole ring have been found tohave exceptional activity.

[0151] The histamine H₃ receptor binding effectiveness of compounds ofthe present invention was determined using the human histamine H₃receptor, Lovenberg et al Mol. Pharmacol. 1999, 1107. Screening usingthe human receptor is particularly important for the identification ofnew therapies for the treatment of human disease. Prior binding assays,for example, relied on rat synaptosomes (Garbarg et al J. Pharmacol.Exp. Ther. 1992, 263, 304), rat cortical membranes (West et al Mol.Pharmacol. 1990, 610), and guinea pig brain (Korte et al Biochem.Biophys. Res. Commun. 1990, 978). A recent comparative study comparinghuman H₃ receptor activity with H₃ receptors from rodent and primatehave shown significant differences in the respective pharmacology of therodent and primate receptors to the human receptor. (West et al Eur. J.Pharmacol. 1999, 233; Lovenberg et al., J. Pharmacol. Exp. Ther. 2000,293, 771-778.)

[0152] The present invention also provides methods useful for thetreatment of diseases or conditions that are modulated by the histamineH₃ receptor including, but not limited to, sleep/wake andarousal/vigilance disorders, migraine, asthma, dementia, mild cognitiveimpairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy,eating disorders, obesity, motion sickness, vertigo, attention deficithyperactivity disorders, learning and memory disorders, schizophrenia,upper airway allergic response, allergic rhinitis, substance abuse,bipolar disorders, manic disorders and depression.

[0153] The present invention also provides compositions and methodsuseful for the treatment of disorders or conditions modulated by thehistamine H₃ receptor in combination with compounds that modulate otherreceptors including, but not limited to, histamine H₁ and histamine H₂receptors. The compounds, compositions and methods of the presentinvention are also useful in the treatment of diseases or conditionsmodulated by the histamine H₃ receptor (such as depression or other CNSdisorders) in combination with compounds that are selective serotoninre-uptake inhibitors (SSRIs), such as PROZAC™, and selectivenorepinephrine uptake inhibitors.

[0154] The present invention provides methods for treating variousdisorders associated with histamine H₃ antagonist activity byadministering a therapeutically effective amount of a compound of thepresent invention, or a composition comprising said compound, to asubject in need of such treatment. Also included in the presentinvention are methods of co-administration, comprising administering atleast one disclosed compound and administering at least one agentselected from a histamine H₁ receptor modulating compound, a histamineH₂ receptor modulating compound, an SSRI (such as PROZAC™), and aselective norepinephrine uptake inhibiting compound; and combinationcompositions thereof. Co-administration includes essentiallysimultaneous administration of either a co-formulated combination orseparate formulations, and administration of separate formulations atdifferent times.

[0155] The present invention provides a method of treating disorders andconditions mediated by the H₃ receptor, particularly a method oftreating attention deficit hyperactivity disorder (ADHD) (i.e. improvingattention and/or memory retention), in a subject in need thereof thatcomprises administering any of the compounds as defined herein in atherapeutically effective amount. The compound may be administered to asubject by any conventional route of administration, including, but notlimited to, intravenous, oral, subcutaneous, intramuscular, intradermaland parenteral. The quantity of the compound that is effective fortreating ADHD is between 0.01 mg per kg and 20 mg per kg of subject bodyweight.

[0156] The present invention provides a method for treating dementiaand/or Alzheimer's disease, wherein a compound of the present inventionacts as a histamine H₃ antagonist (Panula et al Abstr. SocietyNeuroscience, 1995, 21, 1977).

[0157] The present invention provides a method for treating epilepsyaccording to (Yokoyama et al Eur. J. Pharmacol., 1993, 234, 129),wherein a compound of the present invention acts as a histamine H₃antagonist.

[0158] The present invention provides a method for treating narcolepsyand/or eating disorders based on the reference, Machidori et al BrainResearch 1992, 590,180, where a compound of the present invention actsas a histamine H₃ antagonist.

[0159] The present invention provides a method for treating one or moredisorders or conditions selected from a group consisting of motionsickness, vertigo, attention deficit hyperactivity disorders (ADHD), andlearning and memory disorders, wherein a compound of the presentinvention acts as a histamine H₃ antagonist, based on the reference,Barnes et al Abstr. Society Neuroscience, 1993,19,1813.

[0160] The present invention provides a method for treatingschizophrenia based on the reference, Schlicker et alNaunyn-Schmiedeberg's Arch. Pharmacol., 1996, 353, 290-294, wherein acompound of the present invention acts as a histamine H₃ antagonist.

[0161] The present invention provides a method of treating upper airwayallergic response by administering a compound of the present inventionalone, or in combination with a histamine H₁ antagonist. Such utility isreported in U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479.

[0162] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 1 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an entericlayer, which serves to resist disintegration in the stomach and permitsthe inner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

[0163] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyinyl-pyrrolidone or gelatin. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations which generally contain suitable preservatives are employedwhen intravenous administration is desired.

[0164] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0165] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0166] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phophatidylcholines.

[0167] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0168] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of disorders or conditions mediated by thehistamine H₃ receptor (e.g. ADHD) is required.

[0169] The daily dosage of the products may be varied over a wide rangefrom 1 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thesubject to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.02 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.05mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

[0170] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the strength of the preparation, the mode of administration, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust dosages.

[0171] The methods of treatment described in the present invention (e.g.that of ADHD) may also be carried out using a pharmaceutical compositioncomprising any of the compounds as defined herein and a pharmaceuticallyacceptable carrier. The pharmaceutical composition may contain betweenabout 5 mg and 1000 mg, preferably about 10 to 500 mg, of the compound,and may be constituted into any form suitable for the mode ofadministration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

[0172] The present invention also provides isotopically labeledcompounds useful for positron emission tomography (PET), a non-invasivein vivo imaging technique, and/or forabsorption/distribution/metabolism/excretion (ADME) studies. Positronemission tomography uses positron emitting radioisotopes as molecularprobes. When a compound containing positron emitting nuclides, such as¹¹C, ¹³N, ¹⁵O or ¹³F, is administered to a subject, annihilationradiation can be detected electronically using a coincidence technique.PET measurements can, for example, provide information about thelocation and density of receptors. (Phelps, M. E. Proc. Natl. Acad.Sci., 2000, 97, 9226-9233) In the present invention, an appropriatelylabeled compound provides a useful molecular probe and diagnostic toolfor studying central nervous system (CNS) disorders. Of particularinterest are ¹⁸F-labeled compounds, which may be prepared fromnitro-substituted, electron-deficient phenyl precursors by nucleophilicaromatic substitution using [¹⁸F]fluoride ion. Nucleophilicfluorinations may be performed under anhydrous conditions in an inertatmosphere in a non-hydrolytic solvent, usually in the presence of aphase transfer agent, for example, Kryptofix 2.2.2® ortetra-N-butylammonium hydrogen carbonate. (Ding, Y. -S. et al J. Med.Chem., 1991, 34, 767-771).

[0173] References are cited throughout the specification. Thesereferences in their entirety are incorporated by reference into thespecification to more fully describe the state of the art to which itpertains.

[0174] The following examples (Examples I, II, III, IV, V, XI, XII,XIII, XIV, XV, XVI and XVIII) are intended to illustrate but not limitthe invention.

EXAMPLES Example I Preparation of(4-Chloro-phenyl)-[2-(2-dimethylamino-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]methanone

[0175]

[0176] This example teaches the preparation of a compound of Formula Ifollowing Scheme I, wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl;A³ is sulfur; L³ is ethyl; Q³ is dimethylamino; and Q¹ is methyl.

[0177] Step A: Preparation of(4-Chlorophenyl)-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methanol

[0178] 2-Mercapto-1-methylimidazole (1.0 g) in THF (30 mL) under drynitrogen at −78° C. was treated with 1.7M (in pentane) t-butyl lithium(11.3 mL). After stirring for 15 min, the reaction mixture was warmed to0° C. After 30 min, the reaction was cooled to −78° C. and,4-chlorobenzaldehyde (1.5 g) in THF (20 mL) was added dropwise. After 1h, the reaction was quenched with brine (100 mL) and slowly warmed toroom temperature. This mixture was partitioned between diethyl ether(100 mL) and water (25 mL). The organic portion was separated, washedwith brine (50 mL), dried over magnesium sulfate, filtered andevaporated. The residue was suspended in diethyl ether and filtered offto provide as a white powder (4.4 g, 66%) the compound of Formla Iwherein M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³is thiol (SH); L³ is absent; Q³ is absent; and Q¹ is methyl; also knownas, (4-Chlorophenyl)-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methanol. Mcalc=254; M+H found=255. Calculated for C₁₁H₁₁N₂OSCl: C, 51.87; H, 4.35;N, 11.00; found C, 51.97; H, 4.25; N, 10.81.

[0179] Step B: Preparation of(4-Chlorophenyl)-[2-(2-dimethylamino-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol

[0180] The product from Example I, Step A (0.1 g) in acetone (4 mL) wastreated with potassium carbonate (0.5 g) followed by dimethylaminoethylchloride (0.2 g). The mixture was allowed to stir at room temperaturefor 16 h and was then partitioned between ethyl acetate (50 mL) andbrine (50 mL). The organic layer was separated and washed with brine(2×200 mL), dried over sodium sulfate, filtered, and evaporated to givethe crude product. The crude product was purified by silica gelchromatography using 2% Methanol/Dichloromethane as the eluent toprovide 0.08 g (69% yield) of the compound of Formula I wherein M is—CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ is sulfur; L³is ethyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[2-(2-dimethylamino-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol.M calc=325; M+H found=326.

[0181] Step C: Preparation of(4-Chlorophenyl)-[2-(2-dimethylamino-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]methanone

[0182] The product of Example I, Step B (0.07 g) in dichloromethane (2mL) was treated with MnO₂ (0.05 g). The reaction mixture was allowed tostir at room temperature for 1 h. The mixture was filtered through a padof diatomaceous earth (5 g) and concentrated to provide(4-Chloro-phenyl)-[2-(2-dimethylamino-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone(0.06 g, 87%), M calc 323, M+H found=324; ¹H NMR (400 MHz, CDCl₃): δ7.78-7.66 (dm, J=8.5 Hz, 2H), 7.42 (s, 1H), 7.41-7.36 (dm, J=8.7 Hz,2H), 3.82 (s, 3H), 3.38 (t, J=6.7 Hz, 2H), 2.64 (t, J=6.7 Hz, 2H), 2.25(s, 6H). The compound demonstrated useful biological activity whenassessed with a [³H]-N-methylhistamine binding assay (see Table inExample XVIII).

[0183] Step D: Additional Compounds Prepared Following Scheme I andExample I, Steps A, B, and C.

[0184] The following compounds of Formula I were prepared followingScheme I and Example I, Steps A, B, and C; and substituting reagents,and adjusting reaction conditions as needed. The compounds were found tohave useful biological activity based on the K_(i)(nM) value from a[³H]-N-methylhistamine binding assay.

[0185] The compounds of Formula I, wherein:

[0186] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is n-propyl; Q³ is dimethylamino; and Q¹ is methyl; alsoknown as,(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol;M calc=339; M+H found=340; ¹H NMR (400 MHz, CDCl₃): δ 7.26-7-7.20 (m,4H), 6.44 (s, 1H), 5.67 (s, 1H), 3.43 (s, 3H), 2.91 (t, J=7.2 Hz, 2H),2.25-2.21 (t, J=7.4 Hz, 2H), 2.05 (s, 6H), 1.71-1.60 (m, 2H);

[0187] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-bromophenyl; A³ isthiol (SH); L³ is absent; Q³ is absent; and Q¹ is methyl; also known as,(4-Bromophenyl)-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methanol; M calc298; M⁻ found=298;

[0188] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is absent; Q³ is 4-methylpentyl; and Q¹ is methyl; also knownas,(4-Chlorophenyl)-[3-methyl-2-(4-methylpentylsulfanyl)-3H-imidazol-4-yl]-methanol;M calc=338; M+H found=339;

[0189] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isabsent; Q³ is 4-methylpentyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(4-methylpentylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=336; M+H found=337;

[0190] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is n-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also knownas,(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanol;M calc=379; M+H found=380; ¹H NMR (400 MHz, CDCl₃): δ 7.32 (s, 4H), 6.55(s, 1H), 5.77 (s, 1H), 3.57 (s, 3H), 3.00 (t, J=7.1 Hz, 2H), 2.34 (m,6), 1.80 (m, 2H), 1.55 (m, 4H), 1.26 (br m, 2H);

[0191] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is ethyl; Q³ is tetrahydropyran-2-yloxy; and Q¹ is methyl;also known as,(4-Chloro-phenyl)-{3-methyl-2-[2-(tetrahydropyran-2-yloxy)-ethylsulfanyl]-3H-imidazol-4-yl}-methanol;M calc=382; M+H found=383; ¹H NMR (400 MHz, CDCl₃): δ 7.35-7.29 (m, 4H),6.52 (s, 1H), 5.78 (s, 1H), 4.59-4.54 (m, 1H), 3.93-3.77 (m, 2H),3.65-3.56 (m, 1H), 3.49-3.40 (m, 1H), 3.49 (s, 3H), 3.22 (t, J=6.6 Hz,2H), 1.85-1.72 (m, 1H), 1.72-1.61 (m, 1H), 1.60-1.45 (m, 4H);

[0192] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is absent; Q³ is 2-hydroxyethyl; and Q¹ is methyl; also knownas,2-{5-[(4-Chlorophenyl)-hydroxy-methyl]-1-methyl-1H-imidazol-2-ylsulfanyl}-ethanol;M calc=298; M+H found=299;

[0193] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is ethyl; Q³ is cyclohexylsulfanyl; and Q¹ is methyl; alsoknown as,(4-Chlorophenyl)-[2-(2-cyclohexylsulfanyl-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol;M calc=396; M+H found=397;

[0194] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isethyl; Q³ is tetrahydropyran-2-yloxy; and Q¹ is methyl; also known as,(4-Chloro-phenyl)-{3-methyl-2-[2-(tetrahydropyran-2-yloxy)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;M calc=380; M+H found=381;

[0195] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isabsent; Q³ is 2-hydroxyethyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[2-(2-hydroxyethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=296; M+H found=297;

[0196] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isethyl; Q³ is cyclohexylsulfanyl; and Q¹ is methyl; also known as,(4-Chloro-phenyl)-[2-(2-cyclohexylsulfany-ethylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;¹H NMR (400 MHz, CDCl₃): δ 7.70 (dm), 7.39 (dm), 3.82 (s), 3.41-3.38(m), 2.90-2.81 (m); and

[0197] M is hydrogen; A³ is sulfur; L³ is n-propyl; Q³ is dimethylamino;and Q¹ is methyl; also known as,Dimethyl-[3-(1-methyl-1H-imidazol-2-ylsulfanyl)-propyl]-amine; Mcalc=199; M+H found=200.

Example II Preparation of(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone

[0198]

[0199] This example demonstrates the preparation of a compound ofFormula I following Scheme I, wherein M is —C(═O)R^(M); R^(M) isp-chlorophenyl; A³ is sulfur; L³ is n-propyl; Q³ is dimethylamino; andQ¹ is methyl. Alternatively, this compound can be prepared followingSchemes II, IX, and X.

[0200] Step A: Preparation of(4-Chlorophenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol

[0201] The product of example I, Step A (0.09 g) in acetone (2 mL) andN,N-dimethylformamide (2 mL) was treated with potassium carbonate (0.2g) followed by 1-bromo-3-chloropropane (0.11 g). The mixture was allowedto stir at room temperature for 16 h and was then partitioned betweenethyl acetate (50 mL) and brine (50 mL). The organic layer was separatedand washed with brine (2×200 mL), dried over sodium sulfate, filtered,and evaporated to give the crude product. The crude product was purifiedby silica gel chromatography using 2-5% Methanol/Dichloromethane as theeluent to provide(4-Chloro-phenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol(0.08 g, 69%); M calc=330; M+H found=331.

[0202] Step B: Preparation of(4-Chloro-phenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone

[0203] The product of Example II, Step A (2.1 g) was subjected to thesame conditions as described in Example I, Step C (MnO₂, 0.3 g) toprovide(4-Chloro-phenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone(1.7 g, 81%).

[0204] Step C: Preparation of(4-Chloro-phenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]methanone

[0205] The product from Example II, Step B (0.42 g) in acetone (25 mL)was treated with potassium carbonate followed by dimethylaminehydrochloride (0.42 g). The mixture was allowed to stir at 60° C.overnight. The reaction mixture was cooled to room temperature anddiluted with ethyl acetate (75 mL) and washed with brine (2×70 mL). Theorganic portion was dried over magnesium sulfate, filtered, andconcentrated to give the crude product. The crude was purified by silicagel chromatography (1-10% methanol (2M ammonia)/dichloromethane) toprovide(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone(25 mg, 6%), M calc=337, M+H found=338; ¹H NMR (400 MHz, CDCl₃): δ7.81-7.73 (dm, J=8.5 Hz, 2H), 7.50 (s, 1H), 7.48-7.44 (dm, J=8.6 Hz,2H), 3.91 (s, 3H), 3.33 (t, J=7.1 Hz, 2H), 2.45 (t, J=7.1 Hz, 2H), 2.27(s, 6H), 2.0-1.91 (m, 2H). The compound demonstrated useful biologicalactivity when assessed with a [³H]-N-methylhistamine binding assay (seeTable in Example XVIII).

[0206] Step D: Additional compounds prepared following Scheme I andExample II, Steps A, B, and C.

[0207] The following compounds of Formula I were prepared followingScheme I and Example II, Steps A, B, and C; and substituting reagents,and adjusting reaction conditions as needed. The compounds were found tohave useful biological activity based on the K_(i)(nM) value from a[³H]-N-methylhistamine binding assay.

[0208] The compounds of Formula I wherein:

[0209] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-bromophenyl; A³ issulfur; L³ is absent; Q³ is 3-chloropropyl; and Q¹ is methyl; also knownas,(4-Bromophenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol;M calc=374; M+H found=375;

[0210] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-bromophenyl; A³ issulfur; L³ is n-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also knownas,(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanol;M calc=423; M+H found=424; ¹H NMR (400 MHz, CDCl₃): δ 7.41 (dd, J=8.6,2.0 Hz, 2H), 7.2 (d, J=8.3 Hz, 2H), 6.5 (s, 1H), 5.69 (s, 1H), 3.39 (s,3H), 2.94 (t, J=7.1 Hz, 2H), 2.26 (m, 6H), 1.72 (m, 2H), 1.47 (m, 4H),1.34 (br m, 2H);

[0211] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is n-propyl; Q³ is 4-morpholinyl; and Q¹ is methyl; alsoknown as,(4-Chlorophenyl)-[3-methyl-2-(3-morpholin-4-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanol;M calc=381; M+H found=382;

[0212] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 4-morpholinyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(3-morpholin-4-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=379; M+H found=380;

[0213] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is sulfur; L³ isn-propyl; Q³ is cyclohexylamino; and Q¹ is methyl; also known as,(4-Bromophenyl)-[2-(3-cyclohexylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=435; M+H found=436;

[0214] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is sulfur; L³ isn-propyl; Q³ is benzylamino; and Q¹ is methyl; also known as,[2-(3-Benzylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-(4-bromo-phenyl)-methanone;M calc=443; M+H found=444;

[0215] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 4-thiomorpholinyl; and Q¹ is methyl; also known as,(4-Bromophenyl)-[3-methyl-2-(3-thiomorpholin-4-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=439; M+H found=440;

[0216] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=377; M+H found=378; ¹H NMR (400 MHz, CDCl₃): δ 7.69 (dd, J=9.0,2.3 Hz, 2H), 7.43 (s, 1H), 7.39 (dd, J=9.0, 2.3 Hz, 2H), 3.82 (s, 3H),3.25 (t, J=7.1 Hz, 2H), 2.41 (br m, 4H), 1.95 (br m, 2H), 1.55 (br m,4H), 1.36 (br m, 2H); and

Example III Preparation of(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-ylMethanone

[0217]

[0218] This example demonstrates the preparation of a compound ofFormula I following Scheme I, wherein M is —C(═O)R^(M); R^(M) isp-bromophenyl; A³ is sulfur; L³ is n-propyl; Q³ is 1-piperidyl; and Q¹is methyl.

[0219] Step A: Preparation of(4-Bromophenyl)-(2-mercapto-3-3-methyl-3H-imidazol-4-yl)-methanol

[0220] The preparation of Example I, Step A was performed employing2-Mercapto-1-methylimidazole (5.0 g) and 4-bromobenzaldehyde (9.7 g) toprovide the above identified compound as a white solid (3.0 g, 23%). Mcalc 298; M+H found=299.

[0221] Step B:(4-Bromophenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol

[0222] The product from Example III, Step A (3.0 g) was subjected to thesame conditions as described in Example II, Step A employing1-bromo-3-chloropropane (3.1 g) to provide the title compound (2.9 g,77%) as a colorless oil. M calc=374; M+H found=375.

[0223] Step C:(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanol

[0224] The product of Example III, Step B (0.11 g) in acetone (5 mL) andN,N-dimethylformamide (5 mL) was treated with piperidine (0.22 g) andpotassium carbonate (1.8 g). The reaction mixture was allowed to stirfor 16 h and then partitioned between ethyl acetate (75 mL) and aqueoussaturated sodium bicarbonate solution (50 mL). The organic portion waswashed with brine (50 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using 2-5% methanol/dichloromethane as theeluent to provide the title compound (0.27 g, 55%). M calc=423; M+Hfound=424.

[0225] Step D:(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone

[0226] The product from Example III, Step C (0.05 g) was subjected tothe same conditions described in Example I, Step C (MnO₂, 0.05 g) toprovide the title compound (0.01 g, 20%). M calc=421; M+H found=422. ¹HNMR (400 MHz, CDCl₃): δ 7.65 (dd, J=8.6, 2.0 Hz, 2H), 7.55 (dd, J=8.6,2.0 Hz, 2H), 7.46 (s, 1H), 3.86 (s, 3H), 3.28 (t, J=7.1 Hz, 2H), 2.36(tm, J=7.0 Hz, 6H), 1.91 (m, 2H), 1.55 (m, 4H), 1.40 (br m, 2H). Thecompound demonstrated useful biological activity when assessed with a[³H]-N-methylhistamine binding assay (see Table in Example XVIII).

[0227] Step E: Additional compounds prepared following Scheme I, andExample III, Steps A, B, C, and D.

[0228] The following compounds of Formula I were prepared followingScheme I and Example III, Steps A, B, C, and D; and substitutingreagents, and adjusting reaction conditions as needed. The compoundswere found to have useful biological activity based on the K_(i)(nM)value from a [³H]-N-methylhistamine binding assay.

[0229] The compounds of Formula I, wherein:

[0230] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is p-chlorophenyl; A³ issulfur; L³ is absent; Q³ is 3-chloropropyl; and Q¹ is methyl; also knownas,(4-Chlorophenyl)-[2-(3-chloro-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanol;M calc=330; M+H found=331;

[0231] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is sulfur; L³ isn-propyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=381; M+H found=382; ¹H NMR (400 MHz, CDCl₃): δ 7.63 (dd, J=25.8,8.7 Hz, 4H), 7.42 (s, 1H), 3.82 (s, 3H), 3.25 (t, J=14.3 Hz, 2H), 2.43(t, J=17.1 Hz, 2H), 2.24 (s, 6H), 1.91 (m, 2H);

[0232] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 1-(3,4-didehydropiperidyl); and Q¹ is methyl; also knownas,(4-Chloro-phenyl)-{2-[3-(3,4-didehydropiperidin-1-yl)-propylsulfanyl]-3-methyl-3H-imidazol-4-yl}-methanone;M calc=375; M+H found=376; ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, J=8.1 Hz,2H), 7.5 (d, J=8.1 Hz, 2H), 6.19 (s, 1H), 5.67 (s, 1H), 4.22 (s, 7H),3.50 (s, 3H);

[0233] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 4-thiomorpholinyl; and Q¹ is methyl; also known as,(4-chloro-phenyl)-[3-methyl-2-(3-thiomorpholin-4-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=395; M+H found=396;

[0234] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 1-[1,4′]Bipiperidyl; and Q¹ is methyl; also known as,[2-(3-[1,4′]Bipiperidinyl-1′-yl-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-methanone;M calc=460; M+H found=461; and

[0235] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is sulfur; L³ isabsent; Q³ is 3-chloropropyl; and Q¹ is methyl; also known as,(4-Bromophenyl)-[2-(3-chloropropylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=372; M+H found=373.

Example IV Preparation of(4-Chloro-phenyl)-{3-methyl-2-[2-(1-methyl-pyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone

[0236]

[0237] This example teaches the preparation of a compound of Formula Ifollowing Scheme II, wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl;A³ is sulfur; L³ is ethyl; Q³ is 2-(1-methyl-pyrrolidyl); and Q¹ ismethyl.

[0238] Step A:(4-Chlorophenyl)-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methanone

[0239] To a −5° C. solution of monomethylamine (186 g, 6 mol) in 2 L ofdiethyl ether was added a solution of p-chlorophenacylbromide (466 g, 2mol) in 6 L of diethyl ether. The temperature was maintained at 0° C.during the addition and stirring was continued for 2 h. The ether andexcess amine were distilled in vacuo leaving a slurry (3 L). The slurrywas added to cold formyl acetic anhydride, which was prepared by heatinga solution of acetic anhydride (816 mL) and formic acid (98%, 354 mL).The mixture was stored in the refrigerator overnight. The solids werethen filtered and extracted with benzene. The ether was distilled invacuo and the residue was dissolved in benzene and washed thoroughlywith water and brine. The solution was dried over magnesium sulfate andcharcoal. After filtration and evaporation of the solvent, the oil wasdissolved in diethyl ether and seeded. The product precipitated and wasfiltered, and washed with diethyl ether to produce adduct 8 (155 g).This compound was carried on without further purification.

[0240] To a solution of dry benzene (25 mL) was added NaH (54.4%, 1.06g), followed by absolute ethanol (1.15 g). After H₂ evolution ceased,ethyl formate (5.92 g) was added followed by adduct 8 (4.23 g). Themixture was allowed to stir for 72 h. The solvent was then evaporatedand the residue was treated with water and benzene/diethyl ether (1:1).The aqueous layer was acidified and the organic layer was extracted with1 N sodium hydroxide twice. The combined aqueous extracts wereacidified, ethanol (95%) was added with warming until the solution washomogeneous. Potassium thiocyanate (4.0 g) was added and after 2.5 h ofheating on a steam bath, the crystals were collected to provideimidazole 9 (0.7 g)(4-Chlorophenyl)-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methanone. Mcalc=252; M+H found=253.

[0241] Step B: Preparation of(4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone

[0242] The product from Example IV, Step A (0.15 g) was subjected to thesame conditions as described in Example II, Step C, using2-(2-chloroethyl-1-methyl-pyrrolidine hydrochloride (0.16 g) to provide(4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone(0.025 g, 11%). M calc=363; M+H found 364. ¹H NMR (400 MHz, CDCl₃): δ7.68 (dd, J=8.9, 2.2 Hz, 2H), 7.43 (s, 1H), 7.38 (dd, J=9.0, 2.3 Hz,2H), 3.82 (s, 3H), 3.28 (m, 1H), 3.15 (m, 1H), 3.04 (m, 1H), 2.28 (s,3H), 2.15 (br m, 1H), 2.05 (br m, 1H), 1.95 (br m, 1H), 1.65 (br m, 3H),1.48 (br m, 1H). The compound demonstrated useful biological activitywhen assessed with a [³H]-N-methylhistamine binding assay (see Table inExample XVIII).

[0243] Step C: Additional compounds prepared following Scheme II, andExample IV, Steps A, and B.

[0244] The following compounds of Formula I were prepared followingScheme II and Example IV, Steps A and B; and substituting reagents, andadjusting reaction conditions as needed. The compounds were found tohave useful biological activity based on the K_(i)(nM) value from a[³H]-N-methylhistamine binding assay.

[0245] The compounds of Formula I, wherein:

[0246] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ is2-methylpropyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Chloro-phenyl)-[2-(3-dimethylamino-2-methyl-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=351; M+H found=352; ¹H NMR (400 MHz, CDCl₃): δ 7.69 (dd, J=9.1,2.5 Hz, 2H), 7.42 (s, 1H), 7.39 (dd, J=9.1, 2.3 Hz, 2H), 3.84 (s, 3H),3.46 (dd, J=12.9, 5.3 Hz, 1H), 3.05 (m, 1H), 2.20 (br m, 9H), 1.0 (d,J=7.1 Hz, 3H);

[0247] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isabsent; Q³ is 4-(1-methyl-piperidyl); and Q¹ is methyl; also known as,(4-Chloro-phenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=349; M+H found=350; ¹H NMR (400 MHz, CDCl₃): δ 7.72 (dd, J=8.9,2.3 Hz, 2H), 7.47 (s, 1H), 7.41 (dd, J=9.0, 2.3 Hz, 2H), 3.86 (s, 3H),3.75 (br s, H), 2.77 (br m, 2H), 2.28 (s, 3H), 2.15 (br m, 2H), 1.90 (brm, 2H);

[0248] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is 1-(4-methyl-piperazyl); and Q¹ is methyl; also known as,(4-Chloro-phenyl)-{3-methyl-2-[3-(4-methyl-piperazin-1-yl)-propylsulfanyl]-3H-imidazol-4-yl}-methanone;M calc=392; M+H found 393; ¹H NMR (400 MHz, CDCl₃): δ 7.77-7.72 (dm,J=8.5 Hz, 2H), 7.47 (s, 1H), 7.46-7.42 (dm, J=8.5 Hz, 2H), 3.87 (s, 3H),3.30 (t, J=7.1 Hz, 2H), 2.63-2.32 (m, 8H), 2.28 (s, 3H), 1.97-1.89 (m,2H); and

[0249] M is —C(═O)R^(M); R^(M) is phenyl; A³ is sulfur; L³ is n-propyl;Q³ is dimethylamino; and Q¹ is methyl; also known as,[2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;M calc=303; M+H found=304; ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, J=7.7 Hz,2H), 7.41 (m, 1H), 7.30 (m, 3H), 3.73 (s, 3H), 3.15 (t, J=7.14 Hz, 2H),2.1 (br m, 6H), 1.85 (br m, 2H), 1.1 (br m, 2H).

Example V Preparation of(4-Chlorophenyl)-[2-(1-isopropylpiperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone

[0250]

[0251] This example teaches the preparation of a compound of Formula Ifollowing Scheme III, wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl;A³ is oxygen; L³ is methyl, Q³ is 4-(1-isopropyl-piperidyl); and Q¹ ismethyl.

[0252] Step A: Preparation of(4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanol

[0253] The product of Example I, Step A (3.35 g) was subjected to thesame conditions as described in Example I, Step B except thatbromopropane (1.4 mL) was employed as the alkylating agent to provide(4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanol(2.69 g, 71%). M calc=296; M+H found=297. Calculated for C₁₄H₁₇N₂OSCl:C, 56.65; H, 5.77, 9.44; found C, 55.88; H, 5.88; N, 9.84.

[0254] Step B: Preparation of(4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanone

[0255] The product of Example V, Step A (2.69 g) was subjected to thesame conditions as described in Example I, Step C (MnO₂, 3.39 g) toprovide(4-Chlorophenyl)-(3-methyl-2-propylsulfanyl-3H-imidazol-4-yl)-methanone(2.67 g, 85%). M calc=294; M+H found=295. Calculated for C₁₄H₁₅N₂OSCl:C, 57.04; H, 5.13, 9.50; found C, 57.23; H, 4.99; N, 9.43.

[0256] Step C: Preparation of(4-Chlorophenyl)-[3-methyl-2-(propane-1-sulfonyl)-3H-imidazol-4-yl]-methanone

[0257] The product of Example V, Step B (2.26 g) in dichloromethane (300mL) at 0° C. was treated with 3-chloroperoxybenzoic acid, 57% (2.58 g).After 2 h, the reaction mixture was warmed to room temperature. Afterstirring overnight, additional 3-chloroperoxybenzoic acid, 57% (1.6 g)was added. After 4 h, the reaction mixture was partitioned betweendichloromethane and aqueous saturated sodium bicarbonate solution. Theorganic portion was separated, washed three times with aqueous saturatedsodium bicarbonate solution, dried over sodium sulfate, filtered andevaporated to provide(4-Chloro-phenyl)-[3-methyl-2-(propane-1-sulfonyl)-3H-imidazol-4-yl]-methanone(2.3 g, 93%). M calc=326; M+H found=327. Calculated for C₁₄H₁₅N₂OSCl: C,51.45; H, 4.63; N, 8.57; found C, 51.73; H, 4.55; N, 8.56. ¹H NMR (400MHz, CDCl₃): δ 7.98 (d, 2H), 7.68 (d, 2H), 7.44 (s, 1H), 4.46 (s, 3H),3.76-3.70 (m, 2H), 1.95-1.83 (m, 2H), 1.29 (t, 3H).

[0258] Step D: Preparation of(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone

[0259] (1-Isopropyl-piperidin-4-yl)-methanol (0.08 g) in THF (10 mL) wastreated with NaH (60% in mineral oil, 0.02 g). After 30 min, thereaction mixture was cooled to 0° C. and the product of Example V, StepC (0.125 g) in THF (5 mL) was added. After stirring overnight, thereaction mixture was partitioned between brine and ethyl acetate. Theorganic portion was separated, washed twice with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bycolumn chromatography with silica gel using a gradient elution of 1-4%methanol in dichloromethane to provide(4-Chloro-phenyl)-[2-(1-isopropylpiperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone(0.07, 51%) as a white solid. M calc=375; M+H found=376. ¹H NMR (400MHz, CDCl₃): δ 7.66 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.13 (s,1H), 4.24 (d, J=6.1 Hz, 2H), 3.69 (s, 3H), 2.88 (br d, J=11.0 Hz, 2H),2.69 (m, 1H), 2.12 (br dd, J=12.6, 9.6 Hz, 2H), 1.88-1.69 (br m, 1H),1.37 (br dd (J=23.2, 9.3 Hz, 2H), 0.99 (d, J=6.6 Hz, 6H). The compounddemonstrated useful biological activity when assessed with a[³H]-N-methylhistamine binding assay (see Table in Example XVIII).

[0260] Step E: Additional compounds prepared following Scheme III, andExample V, Steps A, B, C, and D.

[0261] The following compounds of Formula I were prepared followingScheme III and Example V, Steps A, B, C, and D; and substitutingreagents, and adjusting reaction conditions as needed. The compoundswere found to have useful biological activity based on the K_(i)(nM)value from a [³H]-N-methylhistamine binding assay.

[0262] The compounds of Formula I, wherein:

[0263] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfoxide (S═O);L³ is absent; Q³ is methyl; and Q¹ is methyl; also known as,(4-Chloro-phenyl)-(2-methanesulfinyl-3-methyl-3H-imidazol-4-yl)-methanone;M calc=282; M+H found=283;

[0264] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is oxygen; L³ isethyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(2-piperidin-1-yl-ethoxy)-3H-imidazol-4-yl]-methanone;M calc=347; M+H found=348; ¹H NMR (400 MHz, CDCl₃): δ 7.67 (dm, J=8.6Hz, 2H), 7.37 (dm, J=8.6 Hz, 2H), 7.14 (s, 1H), 4.52 (t, J=5.8 Hz, 2H),3.69 (s, 3H), 2.74 (t, J=5.8 Hz, 2H), 2.49-2.40 (m, 4H), 1.57-1.48 (m,4H), 1.42-1.32 (m, 2H);

[0265] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-methanone;M calc=361; M+H found=362; ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d, J=8.6 Hz,2H), 7.38 (d, J=8.6 Hz, 2H), 7.14 (s, 1H), 4.44 (t, J=7.0 Hz, 2H), 3.67(s, 3H), 2.40 (t, J=7.3 Hz, 2H), 2.37-2.29 (br m, 2H), 2.00-1.91 (m,2H), 1.57-1.48 (m, 4H), 1.41-1.33 (m, 2H);

[0266] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is NH; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylamino)-3H-imidazol-4-yl]-methanone;¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.1 Hz,2H), 7.21 (s, 1H), 4.51 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 2.47-2.32 (tm,J=6.8 Hz, 6H), 2.10-1.95 (m, 2H), 1.66-1.53 (m, 4H), 1.49-1.37 (m, 2H);

[0267] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-methanone;M calc=405; M+H found=406;

[0268] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ isabsent; Q³ is 4-(1-isopropyl-piperidyl); and Q¹ is methyl; also knownas,(4-Bromo-phenyl)-[2-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=405; M+H found=406; ¹H NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=8.3,2.0 Hz, 2H), 7.54 (dd, J=8.6, 2.0 Hz, 2H), 7.14 (s, 1H), 4.93 (m, 1H),3.68 (s, 3H), 2.78-2.62 (m, 3H), 2.38 (brt, J=8.6 Hz, 2H), 2.13-1.99 (m,2H), 1.88-1.75 (m, 2H), 0.99 (d, J=6.6 Hz, 6H);

[0269] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropyl-piperidyl); and Q¹ is methyl; also knownas,(4-Bromophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=419; M+H found=420; ¹H NMR (400 MHz, CDCl₃): δ 7.59 (dd, J=8.1,2.0 Hz, 2H), 7.54 (dd, J=8.6, 1.8 Hz, 2H), 7.13 (s, 1H), 4.24 (d, J=6.0Hz, 2H), 3.68 (s, 3H), 2.88 (br d, J=11.9 Hz, 2H), 2.74-2.62 (m, 1H),2.11 (td, J=11.9, 2.5 Hz, 2H), 1.85-1.71 (br m, 3H), 1.37 (br dd,J=12.4, 3.5 Hz, 2H), 0.99 (d, J=6.8 Hz, 6H);

[0270] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is oxygen; L³ isn-propyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[2-(3-dimethylamino-propoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=321; M+H found=322; ¹H NMR (400 MHz, CD₃OD): δ 7.78-7.72 (dm,J=8.4 Hz, 2H), 7.48-7.43 (dm, J=6.7 Hz, 2H), 7.22 (s, 1H), 4.53 (t,J=6.2 Hz, 2H), 3.75 (s, 3H), 2.46 (t, J=7.1 Hz, 2H), 2.27 (s, 6H),2.08-1.73 (m, 2H);

[0271] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 1-tert-butoxycarbonyl-piperidin-4-yl; and Q¹ is methyl;also known as,4-[5[(4-bromobenzoyl)-1-methyl-1H-imidazol-2-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester; M calc=477; M+H found=478;

[0272] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ isethyl; Q³ is 1-(4-isopropylpiperazyl); and Q¹ is methyl; also known as,(4-Bromophenyl)-{2-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-3-methyl-3H-imidazol-4-yl}-methanone;M calc=434; M+H found=435; ¹H NMR (400 MHz, CDCl₃): δ 7.62-7.57 (dm,J=8.4 Hz, 2H), 7.57-7.52 (dm, J=8.3 Hz, 2H), 7.14 (s, 1H), 4.52 (t,J=5.7 Hz, 2H), 3.68 (s, 3H), 2.77 (t, J=5.7 Hz, 2H), 2.64-2.40 (m, 8H),1.85 (br s, 1H), 0.98 (d, J=6.5 Hz, 6H);

[0273] M is —C(═O)R^(M); R^(M) is phenyl; A³ is oxygen; L³ is n-propyl;Q³ is 1-piperidyl; and Q¹ is methyl; also known as,[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-phenyl-methanone;M calc=327; M+H found=328; and

[0274] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ isethan-1-yl-2-ylidene; Q³ is 4-(1-isopropyl-piperidyl); and Q¹ is methyl;also known as,(4-Bromophenyl)-{2-[2-(1-isopropyl-piperidin-4-ylidene)-ethoxy]-3-methyl-3H-imidazol-4-yl}-methanone;¹H NMR (400 MHz, CDCl₃): δ 7.57 (dd, J=22.4, 8.4 Hz, 4H), 7.14 (s, 1H),5.43 (t, J=7.2 Hz, 1H), 4.90 (d, J=7.1 Hz, 1H), 3.68 (s, 3H), 2.74-2.65(m, 1H), 2.46 (ddd, J=11.2, 5.5, 5.5 Hz, 4H), 2.32 (t, J=5.5 Hz, 2H),2.23 (t, J=5.5 Hz, 2H), 0.97 (d, J=6.6 Hz, 6H).

[0275] Step F: Additional Compounds that can be Prepared FollowingScheme III and Example V, Steps A, B, C, and D, and E.

[0276] The following compound of Formula I was prepared by firstfollowing Scheme III and Example V, Steps A, B, C, D, and E to prepare4-[5[(4-bromobenzoyl)-1-methyl-1H-imidazol-2-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (see Step E above). This intermediate was thentreated with trifluoroacetic acid in dichloromethane under standardtert-butoxycarbonyl removal conditions to yield the compound of FormulaI wherein:

[0277] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-piperidyl; and Q¹ is methyl; also known as,(4-Bromophenyl)-[3-methyl-2-(piperidin-4-ylmethoxy)-3H-imidazol-4-yl]-methanone;¹H NMR (400 MHz, CDCl₃/CD₃OD (˜1:1)): δ 7.57 (m, 4H), 7.13 (s, 1H), 4.27(d, 2H), 3.69 (s, 3H), 3.40 (m, 2H), 2.86 (m, 2H), 2.10 (brs, 1H), 1.96(m, 2H), 1.59 (m, 2H).

[0278] Step G: Additional Compounds that can be Prepared FollowingScheme III and Example V, Steps A, B, C, D, E and F.

[0279] The following compounds of Formula I were prepared by firstfollowing Scheme III and Example V, Steps A, B, C, D, E, and F toprepare(4-Bromophenyl)-[3-methyl-2-(piperidin-4-ylmethoxy)-3H-imidazol-4-yl]-methanone(see Step F above). This intermediate was then subjected to thereductive amination procedure outlined in Example XV, using theappropriate aldehydes to yield the compounds of Formula I wherein:

[0280] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ isethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,(4-Bromophenyl)-{2-[2-(1-isopropyl-piperidin-4-yl)-ethoxy]-3-methyl-3H-imidazol-4-yl}-methanone;M calc=433; M+H found=434; ¹H, (500 MHz, CDCl₈): δ 7.62-7.57 (dm, J=8.5Hz, 2H), 7.56-7.53 (dm, J=8.5 Hz, 2H), 7.12 (s, 1H), 4.44 (t, J=6.6 Hz,2H), 3.68 (s, 3H), 3.12-2.72 (m, 3H), 2.36-2.10 (m, 2H), 1.88-1.64 (m,3H), 1.18-0.97 (m, 6H);

[0281] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-ethyl-piperidyl); and Q¹ is methyl; also known as,(4-Bromophenyl)-[2-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;¹H NMR (400 MHz, CDCl₃): δ 7.35 (s, 4H), 6.69 (s, 1H), 5.83 (s, 1H),3.49 (s, 3H), 3.08 (m, 2H), 1.65 (m, 3H), 1.53 (m, 2H), 1.27 (m, 3H),0.86 (d, J=6.6 Hz, 6H);

[0282] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-sec-butyl-piperidyl); and Q¹ is methyl; also knownas,(4-Bromophenyl)-[2-(1-sec-butyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;¹H NMR (400 MHz, CDCl₃): δ 7.70 (dd, J=8.3, 2.3 Hz, 2H), 7.65 (dd,J=8.6, 2.0 Hz, 2H), 7.30 (s, 1H), 4.35 (d, J=6.3 Hz, 2H), 3.8 (s, 3H),2.9 (br m, 1H), 2.85 (br m, 2H), 0.9 (m, 3H), 0.8 (m, 3H);

[0283] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-methyl-piperidyl); and Q¹ is methyl; also known as,(4-Bromophenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylmethoxy)-3H-imidazol-4-yl]-methanone; ¹H NMR (400 MHz, CDCl₃): δ 7.58(dd, J=20.9, 8.8 Hz, 4H), 7.14 (s, 1H), 4.26 (d, J=6.1 Hz, 2H), 3.69 (s,3H), 2.85 (d, J=11.4 Hz, 2H), 1.58 (br s, 5H), 1.40 (m, 3H);

[0284] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-[1-(3-methylbutyl)-piperidyl]; and Q¹ is methyl; alsoknown as,(4-Bromophenyl)-{3-methyl-2-[1-(3-methyl-butyl)-piperidin-4-ylmethoxy]-3H-imidazol-4-yl}-methanone;M calc=447; M+H found=448;

[0285] M is —C(═O)R^(M); R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1′-isopropyl-[1,4′]bipiperidyl); and Q¹ is methyl; alsoknown as,(4-Bromophenyl)-[2-(1′-isopropyl-[1,4′]bipiperidinyl-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=502; M+H found=503; and

[0286] M is —C(═O)R¹; R^(M) is p-bromophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-cyclohexyl-piperidyl); and Q¹ is methyl; also knownas,(4-Bromophenyl)-[2-(1-cyclohexyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=459; M+H found=460; ¹H NMR (400 MHz, CDCl₃): δ 7.62-7.57 (m, 2H),7.56-7.51 (m, 2H), 7.14-7.11 (m, 1H), 4.32-4.21 (m, 2H), 3.71-3.66 (m,3H), 3.20-3.03 (m, 1H), 3.00-2.87 (m, 1H), 2.57-2.46 (m, 1H), 2.46-2.25(m, 1H), 2.05-1.88 (m, 2H), 1.88-1.69 (m, 4H), 1.69-1.42 (m, 6H),1.32-1.13 (m, 3H), 1.13-1.10 (m, 1H).

Example XI Preparation of(4-Chlorophenyl)-[2-(1-isopropyl-piperidin4-yloxy)-3-methyl-3H-imidazol-4-yl]-methanone

[0287]

[0288] This example teaches the preparation of a compound of Formula Ifollowing Scheme IX, wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl;A³ is oxygen; L³ is absent; Q³ is 1-isopropyl-piperidin-4-yl; and Q¹ ismethyl.

[0289] Step A: Preparation of 1-Methyl-2-phenylsulfanyl-1H-imidazole

[0290] To a stirred solution of 1-Methyl-1H-imidazole (3.00 mL) in dryTHF (120 mL) was added at −78° C. n-BuLi (15.0 mL, 2.50 M in hexanes).The reaction solution was stirred for 20 minutes at −78° C. anddiphenyldisulfide (8.21 g) was added. The reaction mixture was stirredfor 15 minutes at −78° C. and was allowed to warm to room temperatureover 45 minutes. Water (25.0 mL) was added and the solvent was removedin vacuo. The residue was dissolved in dichloromethane (500 mL) and theorganic layer was washed with water (2×50.0 mL). The organic layer wasdried over magnesium sulfate and the solvent was removed in vacuo. Theresidue was purified by flash chromatography on silica gel(hexanes/acetone) to give the title compound (5.85 g).

[0291] Step B: Preparation of(4-Chlorophenyl)-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-methanol

[0292] To a stirred solution of 2,2,6,6-tetramethylpiperidine (3.54 mL)in dry THF (50.0 mL) and 1,2-dimethoxyethane (DME, 20.0 mL) was added at−78° C. n-BuLi (8.00 mL, 2.50 M in hexanes). The solution was stirredfor 15 minutes at −78° C. and a solution of the product of Example XI,Step A (3.81 g) in dry THF (5.00 mL) was added at −78° C. The reactionmixture was allowed to warm to room temperature and was stirred for 12 hat room temperature. Water (10.0 mL) was added and the solvent wasremoved in vacuo. The residue was dissolved in dichloromethane (650 mL)and the organic layer was washed with water (2×150 mL). The organiclayer was dried over magnesium sulfate and the solvent was removed invacuo. The residue was purified by flash chromatography on silica gel(hexanes/acetone) to give the title compound (4.60 g).

[0293] Step C: Preparation of(4-Chlorophenyl)-(3-methyl-2-phenylsulfanyl-3H-imidazol-4-yl)-methanone

[0294] To a stirred solution of the product of Example XI, Step B (1.00g) in dry dichloromethane (250.0 mL) was added at room temperature MnO₂(3.02 g). The reaction mixture was stirred for 24 h at room temperatureand was filtered through diatomaceous earth. The solvent was removed invacuo and the residue was purified by flash chromatography(hexanes/acetone) to give the title compound (620 mg).

[0295] Step D: Preparation of(2-Benzenesulfonyl-3-methyl-3H-imidazol-4-yl)-(4-chlorophenyl)-methanone

[0296] To a stirred solution of the product of Example XI, Step C (620mg) in diethyl ether (100 mL) was added at room temperature3-chloroperoxybenzoic acid (57%, 2.86 g). The reaction solution wasstirred for 6 h at room temperature and diethyl ether (650 mL) wasadded. The organic layer was washed with saturated sodium bicarbonate(3×150 mL), water (150 mL) and brine (150 mL) and was dried overmagnesium sulfate. The solvent was removed in vacuo and the residue waspurified by flash chromatography on silica gel (hexanes/acetone) to givethe material (802 mg) containing the title compound, which was usedwithout additional purification.

[0297] Step E: Preparation of(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3H-imidazol-4-yl]-methanone

[0298] To a stirred solution of 1-isopropyl-piperidin-4-ol (301 mg) indry THF (10.0 mL) was added at room temperature NaH (60% dispersion inmineral oil, 76.0 mg). The reaction mixture was stirred for 30 minutesat room temperature and a solution of the product of Example XI, Step D(150 mg) in dry THF (1.00 mL) was added. The reaction mixture wasstirred for 18 h at room temperature and water (1.00 mL) was added. Thesolvent was removed in vacuo and the residue was dissolved indichloromethane (300 mL). The organic layer was washed with saturatedsodium bicarbonate (2×50.0 mL) and water (50.0 mL) and was dried overmagnesium sulfate. The solvent was removed in vacuo and the residue waspurified by flash chromatography on silica gel (CHCl₃/NH₃, 2 M inmethanol) to give the title compound (82.0 mg) M calc=361, M+H found362; ¹H NMR (400 MHz, CD₃OD): δ 7.83-7.76 (dm, J=8.4 Hz, 2H), 7.57-7.50(dm, J=9.0 Hz, 2H), 7.26 (s, 1H), 4.50-4.92 (m, 1H), 3.75 (s, 3H),2.92-2.70 (m, 3H), 2.59-2.45 (m, 2H), 2.20-2.04 (m, 2H), 2.00-1.80 (m,2H), 1.11 (d, J=6.5 Hz, 6H). The compound demonstrated useful biologicalactivity when assessed with a [³H]-N-methylhistamine binding assay (seeTable in Example XVIII).

[0299] Step F: Additional Compounds Prepared Following Scheme IX, andExample XI, Steps A, B, C, D, and E.

[0300] The following compounds of Formula I were prepared followingScheme IX and Example XI, Steps A, B, C, D, and E; and substitutingreagents, and adjusting reaction conditions as needed. The compoundswere found to have useful biological activity based on the K_(i)(nM)value from a [³H]-N-methylhistamine binding assay.

[0301] The compounds of Formula I, wherein:

[0302] M is —C(═O)R^(M); R^(M) is methyl; A³ is sulfur; L³ is n-propyl;Q³ is dimethylamino; and Q¹ is methyl; also known as,1-[2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-ethanone;M calc=241; M+H found=242; ¹H NMR (400 MHz, CDCl₃): δ 7.76 (s, 1H), 3.83(s, 3H), 3.39 (t, J=6.4 Hz, 2H), 2.43-2.38 (m, 5H), 2.23 (s, 6H),1.95-1.88 (m, 2H);

[0303] M is —C(═O)R^(M); R¹ is p-chlorophenyl; A³ is sulfur; L³ isn-propyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=337; M+H found=338; ¹H NMR (400 MHz, CDCl₃): δ 7.81-7.73 (dm,J=8.5 Hz, 2H), 7.50 (s, 1H), 7.48-7.44 (dm, J=8.6 Hz, 2H), 3.91 (s, 3H),3.33 (t, J=7.1 Hz, 2H), 2.45 (t, J=7.1 Hz, 2H), 2.27 (s, 6H), 2.0-1.91(m, 2H);

[0304] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is oxygen; L³ isabsent; Q³ is 4-(piperidin-1-ylmethyl)phenyl; and Q¹ is methyl; alsoknown as,(4-Chlorophenyl)-[3-methyl-2-(4-piperidin-1-ylmethyl-phenoxy)-3H-imidazol-4-yl]-methanone;M calc=409; M+H found=410;

[0305] M is —C(═O)R^(M); R^(M) is methyl; A³ is oxygen; L³ is propyl; Q³is 1-piperidyl; and Q¹ is methyl; also known as,1-[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-ethanone; Mcalc=265; M+H found=266; and

[0306] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isabsent; Q³ is 4-(1-isopropyl-piperidyl); and Q¹ is methyl; also knownas,(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone,M calc=377; M+H found=378; ¹H NMR (400 MHz, CD₃OD): δ 7.85-7.79 (dm,J=8.4 Hz, 2H), 7.58-7.51 (m, 3H), 3.94 (s, 3H), 3.68-3.63 (m, 1H),2.97-2.86 (m, 2H), 2.80-2.72 (m, 1H), 2.38 (t, J=10.9 Hz, 2H), 2.17-2.05(m, 2H), 1.82-1.68 (m, 2H), 1.09 (d, J=6.6 Hz, 6H).

[0307] Step G: Additional Compounds that can be Prepared FollowingScheme IX and Example XI, Steps A, B C, D, and E.

[0308] The following compound of Formula I was prepared by firstfollowing Scheme IX and Example XI, Steps A, B, C, D, and E to preparethe compound wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ issulfur; L³ is n-propyl; Q³ is 2-(1,3-dioxolanyl); and Q¹ is methyl (thatis,(4-Chlorophenyl)-[2-(3-[1,3]dioxolan-2-yl-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone).M calc=366; M+H found=367. The dioxolane of the intermediate was thenremoved under the standard mild conditions of pyridiniump-toluenesulfonate (PPTS). Subsequent reductive amination conditions asdescribed in Example XV using piperidine as the basic component providedthe compound of Formula I wherein:

[0309] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is sulfur; L³ isn-butyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[3-methyl-2-(4-piperidin-1-yl-butylsulfanyl)-3H-imidazol-4-yl]-methanone;M calc=391; M+H found=392; ¹H NMR (400 MHz, CD₃OD): δ 7.81 (d, J=8.4 Hz,2H), 7.53 (d, J=8.4 Hz, 3H), 7.54 (s, 1H), 3.90 (s, 3H), 3.31-3.25 (m,2H), 2.66-2.50 (m, 4H), 2.48-2.44 (m, 2H), 1.80-1.68 (m, 4H), 1.68-1.58(m, 4H), 1.54-1.44 (m, 2H).

Example XII Preparation of[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-naphthalen-1-yl-methanone

[0310]

[0311] This example teaches the preparation of a compound of Formula Ifollowing Scheme X, wherein M is —C(═O)R^(M); R^(M) is 1-naphthalenyl;A³ is oxygen; L³ is propyl; Q³ is 1-piperidyl; and Q¹ is methyl.

[0312] Step A: Preparation of 2-Benzenesulfonyl-1-methyl-1H-imidazole

[0313] To a stirred solution of 1-methyl-2-phenylsulfanyl-1H-imidazole(the product of Step A in Example XI) (3.00 g) in diethyl ether (150 mL)was added at room temperature 3-chloroperoxybenzoic acid (57%, 22.7 g).The reaction solution was stirred for 18 h at room temperature anddiethyl ether (750 mL) was added. The organic layer was washed withsaturated sodium bicarbonate (3×200 mL), water (200 mL) and brine (200mL) and was dried over magnesium sulfate. The solvent was removed invacuo and the residue was purified by flash chromatography on silica gel(hexanes/acetone) to give the title compound (2.21 g).

[0314] Step B: Preparation of1-[3-(1-Methyl-1H-imidazol-2-yloxy)-propyl]-piperidine

[0315] To a stirred solution of 3-piperidin-1-yl-propan-1-ol (3.19 g) indry THF (50.0 mL) was added at room temperature NaH (60% dispersion inmineral oil, 800 mg). The reaction mixture was stirred for 30 minutes atroom temperature and a solution of the product of Example XII, Step A(990 mg) in dry THF (20.0 mL) was added. The reaction mixture was heatedunder reflux for 20 h and was allowed to cool to room temperature. Water(10.0 mL) was added and the solvent was removed in vacuo. The residuewas dissolved in dichloromethane (400 mL) and the organic layer waswashed with water (2×100 mL). The organic layer was dried over magnesiumsulfate and the solvent was removed in vacuo. The residue was purifiedby flash chromatography on silica gel (CHCl₃/NH₃, 2 M in methanol) togive 778 mg of the compound of Formula I wherein M is hydrogen; A³ isoxygen; L³ is n-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also knownas, 1-[3-(1-Methyl-1H-imidazol-2-yloxy)-propyl]-piperidine. M calc=223;M+H found=224.

[0316] Step C: Preparation of[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-naphthalen-1-yl-methanol

[0317] To a stirred solution of 2,2,6,6-tetramethylpiperidine (140 mg)in dry THF (5.00 mL) and 1,2-dimethoxyethane (DME, 2.50 mL) was added at−78° C. n-BuLi (467 μL, 1.92 M in hexanes). The solution was stirred for15 minutes at −78° C. and a solution of the product of Example XII, StepB (100 mg) in dry THF (1.00 mL) was added at −78° C. The reactionmixture was stirred for 45 minutes at −78° C. and a solution of1-naphthaldehyde (106 mg) in dry THF (1.00 mL) was added at −78° C. Thereaction mixture was allowed to warm to room temperature and was stirredfor 18 h at room temperature. Water (1.00 mL) was added and the solventwas removed in vacuo. The residue was dissolved in dichloromethane (20.0mL) and the organic layer was washed with water utilizing a Varian chemelute 1005 cartridge. The organic layer was dried over magnesium sulfateand the solvent was removed in vacuo. The residue was purified by flashchromatography on silica gel (CHCl₃/NH₃, 2M in methanol) to give thematerial (35.0 mg) containing the title compound, which was used withoutadditional purification.

[0318] Step D Preparation of[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-naphthalen-1-yl-methanone

[0319] To a stirred solution of the product of Example XII, Step C (35.0mg) in dry dichloromethane (5.00 mL) was added at room temperature MnO₂(85%, activated, 47.0 mg). The reaction mixture was stirred for 18 h atroom temperature and was filtrated over diatomaceous earth. The solventwas removed in vacuo and the residue was purified by flashchromatography (CHCl₃/NH₃, 2M in methanol) to give the title compound(8.00 mg). M calc=377, M+H found=378. ¹H NMR (400 MHz, CD₃OD): δ8.09-8.04 (m, 2H), 7.98-7.95 (m, 1H), 7.69-7.67 (m, 1H), 7.57-7.50 (m,3H), 6.98 (s, 1H), 4.48 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 2.56-2.45 (m,6H), 2.09-2.02 (m, 2H), 1.66-1.60 (m, 4H), 1.51-1.48 (m, 2H). Thecompound demonstrated useful biological activity when assessed with a[³H]-N-methylhistamine binding assay (see Table in Example XVIII).

[0320] Step E: Additional compounds prepared following Scheme X, andExample XII, Steps A, B, C, and D.

[0321] The following compounds of Formula I were prepared followingScheme X and Example XII, Steps A, B, C, and D; and substitutingreagents, and adjusting reaction conditions as needed. The compoundswere found to have useful biological activity based on the K_(i)(nM)value from a [³H]-N-methylhistamine binding assay.

[0322] The compounds of Formula I, wherein:

[0323] M is —C(═O)R^(M); R^(M) is methyl; A³ is oxygen; L³ is propyl; Q³is 1-piperidyl; and Q¹ is methyl; also known as,1-[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-ethanone; Mcalc=265; M+H found=266;

[0324] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is methyl; A³ is oxygen;L³ is propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,1-[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-ethanol; Mcalc=267; M+H found=268; ¹H NMR (400 MHz, CDCl₃): δ 6.47 (s, 1H), 4.73(m, 1H), 4.34 (m, 2H), 3.43 (s, 3H), 2.48-2.36 (m, 6H), 2.02-1.94 (m,2H), 1.63-1.54 (m, 7H), 1.47-1.41 (m, 2H);

[0325] M is —C(═O)R^(M); R^(M) is 4-methoxyphenyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,(4-Methoxyphenyl)-[3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-methanone;M calc=357; M+H found=358;

[0326] M is —C(═O)R^(M); R^(M) is 4-pyridyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-pyridin-4-yl-methanone;M calc=328; M+H found=329;

[0327] M is —C(═O)R^(M); R^(M) is 3-pyridyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-pyridin-3-yl-methanone;M calc=328; M+H found=329;

[0328] M is —C(═O)R^(M); R^(M) is 2-pyridyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-pyridin-2-yl-methanone;M calc=328; M+H found=329; ¹H NMR (400 MHz, CD₃OD): δ 8.69-8.68 (m, 1H),8.02-7.97 (m, 3H), 7.62-7.56 (m, 1H), 4.50 (t, J=6.2 Hz, 2H), 3.79 (s,3H), 2.60-2.48 (m, 6H), 2.12-2.04 (m, 2H), 1.67-1.61 (m, 4H), 1.54-1.46(m, 2H);

[0329] M is —C(═O)R^(M); R^(M) is cyclohexyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,Cyclohexyl-[3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-methanone;M calc=333; M+H found=334;

[0330] M is —C(═O)R^(M); R^(M) is 4-biphenyl; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,Biphenyl-4-yl-[3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-methanone;M calc=403; M+H found=404; ¹H NMR (400 MHz, CD₃OD): δ 7.90-7.86 (m, 2H),7.80-7.77 (m, 2H), 7.72-7.70 (m, 2H), 7.53-7.47 (m, 2H), 7.42-7.38 (m,1H), 7.31 (s, 1H), 4.50 (t, J=6.2 Hz, 2H), 3.77 (s, 3H), 2.59-2.48 (m,6H), 2.11-2.05 (m, 2H), 1.67-1.61 (m, 4H), 1.54-1.48 (m, 2H);

[0331] M is —C(═O)R^(M); R^(M) is hydrogen; A³ is oxygen; L³ isn-propyl; Q³ is 1-piperidyl; and Q¹ is methyl; also known as,3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl-carbaldehyde; Mcalc=251; M+H found=252;

[0332] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is 3,5-dichlorophenyl;A³ is oxygen; L³ is methyl; Q³ is 4-(1-isopropylpiperidyl); and Q ismethyl; also known as,(3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanol;M calc=411; M+H found=412;

[0333] M is —CHOHR^(M); A^(M) is hydroxy; R^(M) is 4-cyanophenyl; A³ isoxygen; L³ is methyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl;also known as,4-{Hydroxy-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methyl}-benzonitrile;¹H NMR (400 MHz, CDCl₃): δ 7.57 (d), 7.48 (d), 6.20 (s), 5.72 (s), 3.13(s), 0.96 (d);

[0334] M is —C(═O)R^(M); R^(M) is 3,5-dichlorophenyl; A³ is oxygen; L³is methyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also knownas,(3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=409; M+H found=410; ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d, J=1.9 Hz,2H), 7.54 (t, J=1.9 Hz, 1H), 7.25 (s, 1H), 4.33 (d, J=6.2 Hz, 2H), 3.76(s, 3H), 3.00-2.85 (m, 2H), 2.80-2.69 (m, 1H), 2.22-2.21 (m, 2H),1.92-1.83 (m, 2H), 1.49-1.39 (m, 2H), 1.07 (d, J=6.6 Hz, 6H).

[0335] M is —C(═O)R^(M); R^(M) is 2-chlorophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,(2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=375; M+H found=376; ¹H NMR (400 MHz, CDCl₃): 7.40-7.29 (m, 2H),28.1-7.22 (m, 2H), 6.89 (s, 1H), 4.24 (d, J=6.2 Hz, 2H), 3.75 (s, 3H),2.91 (br d, J=11.3 Hz, 2H), 2.75-2.70 (m, 1H), 2.24-2.09 (m, 2H), 1.78(br d, J=10.9 Hz, 2H), 1.47-1.38 (m, 2H), 1.03 (d, J=7.6 Hz, 6H);

[0336] M is —C(═O)R^(M); R^(M) is 4-cyanophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,4-[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazole-4-carbonyl]-benzonitrile;M calc=366; M+H found=367; ¹H NMR (400 MHz, CDCl₃): δ 7.81-7.75 (dm,J=8.2 Hz, 2H), 7.72-7.68 (dm, J=11.1 Hz, 2H), 7.12 (s, 1H), 4.25 (d,J=6.2 Hz, 2H), 3.70 (s, 3H), 2.87 (d, J=11.4 Hz, 2H), 2.73-2.60 (m, 1H),2.11 (t, J=11.7 Hz, 2H), 1.85-1.72 (m, 3H), 1.44-1.27 (m, 2H), 0.98 (d,J=8.8 Hz, 6H);

[0337] M is —C(═O)R^(M); R^(M) is 3-chlorophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,(3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=375; M+H found=376; ¹H NMR (400 MHz, CDCl₃): δ 7.69 (t, J=1.7 Hz,1H), 7.61-7.51 (dm, J=7.6 Hz, 1H), 7.48-7.44 (m, 1H), 7.34 (t, J=7.9 Hz,1H), 7.16 (s, 1H), 4.25 (d, J=6.2 Hz, 2H), 3.69 (s, 3H), 2.94-2.83 (m,2H), 2.74-2.64 (m, 1H), 2.18-2.07 (m, 1H), 1.84-1.72 (m, 2H), 1.70-1.32(m, 4H), 1.00 (d, J=6.5 Hz, 6H);

[0338] M is —C(═O)R^(M); R^(M) is 4-trifluoromethylphenyl; A³ is oxygen;L³ is methyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; alsoknown as,[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;M calc=409; M+H found=410; ¹H NMR (400 MHz, CDCl₃): δ 7.83-7.77 (dm,J=8.0 Hz, 2H), 7.74 (d, J=7.6 Hz, 2H), 7.22 (s, 1H), 4.33 (d, J=6.3 Hz,1H), 3.72 (s, 3H), 2.98-2.82 (m, 2H), 2.85-2.66 (m, 1H), 2.25-2.14 (m,2H), 1.90-1.73 (m, 2H), 1.56-1.41 (m, 2H), 1.07 (d, J=6.6 Hz, 6H);

[0339] M is —C(═O)R^(M); R^(M) is 4-nitrophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitro-phenyl)-methanone;M calc=386; M+H found=387; ¹H NMR (400 MHz, CDCl₃): δ 8.27-8.23 (dm,J=8.7 Hz, 2H), 7.88-7.81 (dm, J=8.7 Hz, 2H), 7.14 (s, 1H), 4.26 (d,J=6.2 Hz, 2H), 3.72 (s, 3H), 2.91-2.81 (d, J=11.5 Hz, 2H), 2.15-2.05 (m,2H), 1.84-1.72 (m, 3H), 1.43-1.27 (m, 2H), 0.99 (d, J=6.6 Hz, 6H);

[0340] M is —C(═O)R^(M); R^(M) is 4-fluorophenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=359; M+H found=360; ¹H NMR (400 MHz, CDCl₃): δ 7.78-7.69 (m, 2H),7.12 (s, 1H), 7.11-7.03 (m, 2H), 4.24 (d, J=6.6 Hz, 2H), 3.69 (s, 3H),2.93-2.82 (m, 2H), 2.74-2.61 (m, 1H), 2.11 (t, J=11.4 Hz, 2H), 1.77 (d,J=12.6 Hz, 2H), 1.46-1.29 (m, 2H), 1.23-1.12 (m, 1H), 0.99 (d, J=6.4 Hz,6H); and

[0341] M is —C(═O)R^(M); R^(M) is 4-isopropylphenyl; A³ is oxygen; L³ ismethyl; Q³ is 4-(1-isopropylpiperidyl); and Q¹ is methyl; also known as,(4-Isopropylphenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=383; M+H found=384; ¹H NMR (400 MHz, CDCl₃): δ 7.70-7.55 (m, 2H),7.27-7.22 (m, 2H), 7.17 (s, 1H), 4.28-4.15 (m, 2H), 3.69 (s, 3H),2.98-2.82 (m, 2H), 2.81-2.65 (m, 1H), 2.25-2.05 (m, 3H), 1.85-1.25 (m,5H), 1.23-1.10 (m, 6H), 1.03 (dm J=6.2 Hz, 6H).

Example XIII Preparation of{3-[5-(4-Chlorobenzyl)-1-methyl-1H-imidazol-2-ylsulfanyl]-propyl}-dimethyl-amine

[0342]

[0343] This example teaches the preparation of a compound of Formula Ifollowing Scheme VII, wherein M is —CH₂R^(M); R^(M) is p-chlorophenyl;A³ is sulfur; L³ is n-propyl; Q³ is dimethylamino; and Q¹ is methyl.

[0344] The product from Example II, Step C, (0.04 g) in n-butanol (1 mL)was treated with potassium t-butoxide (0.03 g), followed by hydrazine(0.011 mL). After heating to 120° C. for 16 h, the mixture was cooled toroom temperature and partitioned between brine (75 mL) and ethyl acetate(100 mL). The layers were separated and the organic portion was washedwith brine (100 mL), dried over sodium sulfate, and concentrated to givethe crude product. The crude material was purified by silica gelchromatography (1-5% Methanol/Dichloromethane to provide the titlecompound (0.017 g, 45%). M calc=323; M+H found 324. ¹H NMR (400 MHz,CDCl₃): δ 7.19 (d, J=8.3 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 6.78 (s, 1H),3.81 (s, 2H), 3.29 (s, 3H), 2.98 (t, J=7.3 Hz, 2H), 2.29 (t, J=7.0 Hz,2H), 2.12 (s, 6H), 1.74 (m, 2H). The compound demonstrated usefulbiological activity when assessed with a [³H]-N-methylhistamine bindingassay (see Table in Example XVIII).

Example XIV Preparation of(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone oxime

[0345]

[0346] This example teaches the preparation of a compound of Formula Ifollowing Scheme VIII, wherein M is —C(═N—OH)R^(M); R^(M) isp-chlorophenyl; A³ is sulfur; L³ is n-propyl; Q³ is dimethylamino; andQ¹ is methyl.

[0347] The product from Example II, Step C (0.07 g) in ethanol (2 mL)was treated with hydroxylamine hydrochloride (0.07 g) followed bypyridine (0.08 mL). After stirring for 16 h at 80° C., the solvent wasremoved under reduced pressure. The residue was then partitioned betweenwater (75 mL) and ethyl acetate (100 mL). The layers were separated andthe organic portion was washed with brine (100 mL). The aqueous portionwas treated with solid sodium bicarbonate until the solution reachedpH=7. The aqueous portion was extracted with ethyl acetate (4×50 mL) anddichloromethane (2×50 mL). The combined organic extracts were dried oversodium sulfate, and concentrated to provide the crude product. The crudematerial was purified by silica gel chromatography (1-5% Methanol (2 MNH₃)/dichloromethane to provide the title compound as a mixture of oximeisomers (0.01 g, 14%), M calc=352, M+H found=353; ¹H NMR (400 MHz,CDCl₃): δ 7.43-7.37 (m, 1.4H), 7.32-7.28 (m, 1.3H), 7.25-7.20 (m, 1.3H),6.99 (s, 0.6H), 6.62 (s, 0.4H), 3.66 (s, 1H), 3.26 (s, 2H), 3.12-3.04(m, 2H), 2.47-2.36 (m, 2H), 2.23 (s, 6H), 1.94-1.82 (m, 2H). Thecompound demonstrated useful biological activity when assessed with a[³H]-N-methylhistamine binding assay (see Table in Example XVIII).

Example XV Preparation of[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazol-4-yl]-piperidin-1-yl-methane

[0348]

[0349] This example teaches the preparation of a compound of Formula Ifollowing Scheme XII, wherein M is —CH₂R^(M); R^(M) is 1-piperidyl; A³is oxygen; L³ is n-propyl; Q³ is 1-piperidyl; and Q¹ is methyl.

[0350] To a stirred solution of3-methyl-2-(3-piperidin-1-yl-propoxy)-3H-imidazole-4-carbaldehyde (10.0mg) and piperidine (3.41 mg) in 1,2-dichloroethane was added at roomtemperature sodium triacetoxyborohydride (12.7 mg). The reaction mixturewas stirred for 18 h at room temperature and dichloromethane (5.00 mL)and saturated sodium bicarbonate (2.00 mL) were added. The mixture wasstirred for 1 h at room temperature and additional dichloromethane (100mL) was added. The organic layer was washed with saturated sodiumbicarbonate (20.0 mL) and water (2×20.0 mL) and was dried over magnesiumsulfate. The solvent was removed in vacuo and the residue was purifiedby flash chromatography on silica gel (CHCl₃/NH₃, 2 M in methanol) togive the title compound (1.00 mg). M calc=320; M+H found=321. ¹H NMR(400 MHz, CD₃OD): δ 6.42 (s, 1H), 4.30 (t, J=6.2 Hz, 2H), 3.40 (s, 3H),3.34 (s, 2H), 2.57-2.38 (m, 10H), 2.04-1.96 (m, 2H), 1.67-1.41 (m, 12H).The compound demonstrated useful biological activity when assessed witha [³H]-N-methylhistamine binding assay (see Table in Example XVIII).

Example XVI Preparation of(4-Chloro-phenyl)-[2-(3-dimethylamino-propane-1-sulfinyl)-3-methyl-3H-imidazol-4-yl]-methanone

[0351]

[0352] This example teaches the preparation of a compound of Formula Ifollowing Scheme XI, wherein M is —C(═O)R^(M); R^(M) is p-chlorophenyl;A³ is S(O); L³ is n-propyl; Q³ is dimethylamino; and Q¹ is methyl.

[0353] Step A: Preparation of(4-Chloro-phenyl)-[2-(3-dimethylamino-propane-1-sulfinyl)-3-methyl-3H-imidazol-4-yl]-methanone

[0354] To a stirred solution of(4-Chloro-phenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone(135 mg) in glacial acetic acid (4.00 mL) was added at room temperatureH₂O₂ (82.0 μL; 30 wt. % in water). The reaction solution was stirred for48 h at room temperature, and water (10.0 mL) was added. The solutionwas brought to pH 12 using sodium hydroxide (25% in water) and extractedwith dichloromethane (250 mL, 2×50.0 mL). The combined organic layerswere washed with water (3×20.0 mL) and were dried over magnesiumsulfate. The solvent was removed in vacuo, and the residue was purifiedby flash chromatography on silica gel (CHCl₃/NH₃, 2 M in methanol) togive the title compound (121 mg). M calc=353; M+H found=354. ¹H NMR (400MHz, CD₃OD): δ 7.91-7.87 (m, 2H), 7.70 (s, 1H), 7.60-7.55 (m, 2H), 4.21(s, 3H), 3.61-3.48 (m, 2H), 2.54-2.43 (m, 2H), 2.21 (s, 6H), 2.04-1.94(m, 2H). The compound demonstrated useful biological activity whenassessed with a [³H]-N-methylhistamine binding assay (see Table inExample XVIII).

[0355] Step B: Additional Compounds Prepared Following Scheme XI, andExample XVI, Step A.

[0356] The following compounds of Formula I were prepared followingScheme XI and Example XVI, Step A; and substituting reagents, andadjusting reaction conditions as needed.

[0357] The compounds of Formula I, wherein:

[0358] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is S(O₂); L³ isn-propyl; Q³ is dimethylamino; and Q¹ is methyl; also known as,(4-Chlorophenyl)-12-(3-dimethylamino-propane-1-sulfonyl)-3-methyl-3H-imidazol-4-yl]-methanone;M calc=369; M+H found=370; K_(i)=10000; and

[0359] M is —C(═O)R^(M); R^(M) is p-chlorophenyl; A³ is S(O₂); L³ isn-propyl; Q³ is dimethylazinoyl; and Q¹ is methyl; also known as,(4-Chlorophenyl)-[2-(3-dimethylamino-propane-1-sulfonyl)-3-methyl-3H-imidazol-4-yl]-methanoneoxide; M calc=385; M+H found=386; K_(i)=10000.

EXAMPLE XVIII In vitro Transfection of Cells with Human HistamineReceptor

[0360] A 10 cm tissue culture dish with a confluent monolayer of SK-N-MCcells was split two days prior to transfection. Using sterile techniquethe media was removed and the cells were detached from the dish by theaddition of trypsin. One fifth of the cells were then placed onto a new10 cm dish. Cells were grown in a 37° C. incubator with 5% CO₂ inMinimal Essential Media Eagle with 10% Fetal Bovine Serum. After twodays cells were approximately 80% confluent. These were removed from thedish with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One μg supercoiled H₃ receptor cDNA was added tothe cells and mixed. The voltage for the electroporation was set at 0.25kV, the capacitance is set at 960 μF. After electroporation the cellswere diluted into 10 mL complete media and plated onto four 10 cmdishes. Because of the variability in the efficiency of electroporationfour different concentrations of cells were plated. The ratios usedwere; 1:20, 1:10, 1:5, with the remainder of the cells being added tothe fourth dish. The cells were allowed to recover for 24 h beforeadding the selection media (complete media with 600 μg/mL G418). After10 days dishes were analyzed for surviving colonies of cells. Disheswith well isolated colonies were used. Cells from individual colonieswere isolated and tested. SK-N-MC cells were used because they giveefficient coupling for inhibition of adenylate cyclase. The clones thatgave the most robust inhibition of adenylate cyclase in response tohistamine were used for further study.

[3H]-N-methylhistamine Binding

[0361] Cell pellets from histamine H₃ receptor-expressing SK-N-MC cellswere homogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatants from a 800 gspin were collected, recentrifuged at 30,000 g for 30 minutes. Pelletswere re-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes wereincubated with 0.8 nM [³H]-N-methylhistamine plus/minus test compoundsfor 45 min at 25° C. and harvested by rapid filtration over GF/C glassfiber filters (pretreated with 0.3% polyethylenimine) followed by fourwashes with ice cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine. PK_(i)values were calculated based on a KD of 800 μM and a ligandconcentration ([L]) of 800 μM according to the formula:

K _(i)=(IC₅₀)/(1+([L]/(K _(D))). K_(i) Values Example Compound NameK_(i) (nM) I (4-Chloro-phenyl)-[2-(2-dimethylamino-ethyl- 98sulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone II(4-Chlorophenyl)-[2-(3-dimethylamino- 2propylsulfanyl)-3-methyl-3H-imidazol-4-yl]- methanone II(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl- 3.1propylsulfanyl)-3H-imidazol-4-yl]-methanone III(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl- 7.5propylsulfanyl)-3H-imidazol-4-yl]-methanone III(4-Bromophenyl)-[2-(3-dimethylamino- 1.6propylsulfanyl)-3-methyl-3H-imidazol-4-yl]- methanone IV(4-Chlorophenyl)-{3-methyl-2-[2-(1- 2methylpyrrolidin-2-yl)-ethylsulfanyl]-3H- imidazol-4-yl}-methanone IV[2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H- 4imidazol-4-yl]-phenyl-methanone IV(4-Chlorophenyl)-[3-methyl-2-(1-methyl-piperidin- 74-ylsulfanyl)-3H-imidazol-4-yl]-methanone V(4-Chloro-phenyl)-[2-(1-isopropyl-piperidin-4- 3.7ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone V(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl- 32propylamino)-3H-imidazol-4-yl]-methanone V(4-Bromophenyl)-[2-(1-isopropyl-piperidin-4- 5.3ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone V(4-Bromophenyl)-[2-(1-ethyl-piperidin-4- 6.6ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone V(4-Bromophenyl)-[2-(1-sec-butyl-piperidin-4- 9ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone XI(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4- 25yloxy)-3-methyl-3H-imidazol-4-yl]-methanone XI(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4- 3ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone XII[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H- 79imidazol-4-yl]-naphthalen-1-yl-methanone XII(2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4- 1.3ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone XII(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4- 2.5ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone XII(3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4- 2.8ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone XII(3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4- 4ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone XII[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl- 4.13H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)- methanone XII[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl- 4.63H-imidazol-4-yl]-(4-nitro-phenyl)-methanone XII4-{Hydroxy-[2-(1-isopropyl-piperidin-4-ylmethoxy)- 7.63-methyl-3H-imidazol-4-yl]-methyl}-benzonitrile XIII{3-[5-(4-Chlorobenzyl)-1-methyl-1H-imidazol-2- 22ylsulfanyl]-propyl}-dimethyl-amine XIV(4-Chlorophenyl)-[2-(3-dimethylamino- 3.2propylsulfanyl)-3-methyl-3H-imidazol-4-yl]- methanone oxime XV[3-Methyl-2-(3-piperidin-1-yl-propoxy)-3H- 36.4imidazol-4-yl]-piperidin-1-yl-methane XVI(4-Chlorophenyl)-[2-(3-dimethylamino-propane-1- 315sulfinyl)-3-methyl-3H-imidazol-4-yl]-methanone

What is claimed:
 1. A compound of the formula (I):

wherein: Q¹ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl and C₂₋₇ alkenyl; wherein Q¹ may be substituted with one ormore substituents selected from the group consisting of halo, cyano,hydroxy, OR¹¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino,R¹¹HN—, R¹¹R¹²N—, amido, R¹¹HNC(O), R¹¹R¹²NC(O) and R¹¹OC(O), andwherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅ haloalkyl orC₂₋₅alkenyl; M is a moiety of the formula —CH₂R^(M), —CHOHR^(M),—C(═O)R^(M) or —C(═N—OH)R^(M), wherein, R^(M) is selected from the groupconsisting of C₁₋₇ alkyl, R^(M1)HN—, R^(M1)R^(M2)N—, C₅₋₇cycloalkyl,aryl, biaryl and 4-7 membered heterocyclyl containing between 1 and 2heteroatoms, wherein R^(M) may be substituted with one or moresubstituents independently selected from the group consisting of halo,cyano, hydroxy, OR^(M1), C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl,nitro, amino R^(M1)HN—, R^(M1)R^(M2)N—, amido, R^(M1)HNC(O) andR^(M1)R^(M2)NC(O), and wherein R^(M1) and R^(M2) are independently C₁₋₅alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; or M is hydrogen; A³ is NH, NR³,sulfur, sulfoxide, sulfone or oxygen, wherein R³ is C₁₋₅ alkyl; L³ isC₁₋₇ alkyl or C₂₋₇ alkenyl; wherein L³ may be substituted with one ormore substituents selected from the group consisting of halo, hydroxy,methoxy and amino; or L³ is absent; and Q³ is selected from the groupconsisting of C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl,C₅₋₇cycloalkenyl, aryl, 4-7 membered heterocyclyl, C₃₋₇ cycloalkyl-4-7membered heterocyclyl, 4-7 membered heterocyclyl-C₃₋₇ cycloalkyl,bi-(4-7 membered heterocyclyl), R³¹HN—, R³¹R³²N—, azinoyl,C₃₋₇cycloalkylamino, 4-7 membered heterocyclylamino, aryl C₁₋₆alkylamino, C₃₋₇cycloalkylsulfanyl, 4-7 membered heterocyclylsulfanyland 4-7 membered heterocyclyloxy; wherein Q³ may be substituted with oneor more substituents selected from the group consisting of halo, cyano,hydroxy, OR³¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino,R³¹HN—, R³¹R³²N—, amido, R³¹HNC(O), R³¹R³²NC(O), R³¹OC(O), C₃₋₇cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7membered heterocyclylalkyl, and wherein R³¹ and R³² are independentlyC₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; or A³ and L³ are absent andQ³ is sulfanyl; or a pharmaceutically acceptable ester, ether, N-oxide,amide, salt, hydrate or isotopically labeled form thereof.
 2. A compoundof claim 1 of the formula (I):

wherein: Q¹ is C₁₋₃alkyl wherein Q¹ may be substituted with onesubstituent selected from the group consisting of amino, R¹¹HN—,R¹¹R¹²N—, amido, R¹¹HNC(O), R¹¹R¹²NC(O) and R¹¹OC(O), and wherein R¹¹and R¹² are independently C₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; Mis a moiety of the formula —CH₂R^(M), —CHOHR^(M), or —C(═O)R^(M),wherein, R^(M) is selected from the group consisting of C₁₋₃ alkyl,R^(M1)HN—, C₁₋₃ R^(M1)R^(M2)N—, C₅₋₇cycloalkyl, aryl, biaryl and 4-7membered heterocyclyl containing between 1 and 2 heteroatoms, whereinR^(M) may be substituted with one or more substituents independentlyselected from the group consisting of halo, cyano, hydroxy, OR^(M1),C₁₋₅ alkyl, nitro, and amino; and A³ is sulfur or oxygen L³ is C₁₋₇alkyl or C₂₋₇ alkenyl; wherein L³ may be substituted with one or moresubstituents selected from the group consisting of halo, hydroxy,methoxy and amino (H₂N—); or L³ is absent; and Q³ is selected from thegroup consisting of C₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, 4-7 membered heterocyclyl, C₃₋₇cycloalkyl-4-7 membered heterocyclyl, 4-7 membered heterocyclyl-C₃₋₇cycloalkyl, bi-(4-7 membered heterocyclyl), R³¹HN—, R³¹R³²N—, azinoyl,C₃₋₇cycloalkylamino, 4-7 membered heterocyclylamino, aryl C₁₋₆alkylamino, C₃₋₇ cycloalkylsulfanyl, 4-7 membered heterocyclylsulfanyland 4-7 membered heterocyclyloxy; wherein Q³ may be substituted with oneor more substituents selected from the group consisting of halo, cyano,hydroxy, OR³¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino,R³¹HN—, R³¹R³²N—, amido, R³¹HNC(O), R³¹R³²NC(O), R³¹OC(O),C₃₋₇cycloalkyl, monocyclic 4-7 membered heterocyclyl and monocyclic 4-7membered heterocyclylalkyl, and wherein R³¹ and R³² are independentlyC₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; or A³ and L³ are absent andQ³ is sulfanyl; or a pharmaceutically acceptable ester, ether, N-oxide,amide, salt, hydrate or isotopically labeled form thereof.
 3. Thecompound of claim 1 wherein Q¹ is unsubstituted C₁₋₃ alkyl.
 4. Thecompound of claim 1 wherein Q¹ is methyl.
 5. The compound of claim 1wherein M is a moiety of the formula —CH₂R^(M), —CHOHR^(M), —C(═O)R^(M)or —C(═N—OH)R^(M).
 6. The compound of claim 1 wherein M is —CHOHR^(M).7. The compound of claim 1 wherein M is —C(═O)R^(M).
 8. The compound ofclaim 1 wherein R^(M) is unsubstituted or substituted C₃₋₇ cycloalkyl,aryl or 4-7 membered heterocyclyl.
 9. The compound of claim 1 whereinR^(M) is aryl unsubstituted or substituted with halo, cyano, hydroxy,methoxy, C₁₋₃ alkyl, perhalomethyl, nitro, or amino.
 10. The compound ofclaim 1 wherein R^(M) is phenyl unsubstituted or substituted with F, Cl,Br, cyano, methoxy, C₁₋₃ alkyl, CF₃, hydroxy, or nitro.
 11. The compoundof claim 1 wherein A³ is oxygen, sulfur or NH.
 12. The compound of claim1 wherein A³ is oxygen.
 13. The compound of claim 1 wherein A³ issulfur.
 14. The compound of claim 1 wherein L³ is unsubstituted orsubstituted C₁₋₅ alkyl or C₂₋₅ alkenyl.
 15. The compound of claim 1wherein L³ is selected from (a) C₁₋₃ alkyl, which may be unsubstitutedor substituted, and independently may be unbranched or branched, and (b)C₄₋₅ alkyl, which is branched or substituted, or both.
 16. The compoundof claim 1 wherein L³ is absent.
 17. The compound of claim 1 wherein Q³is R³¹HN— or R³¹R³²N—, or an unsubstituted or substitutednitrogen-containing 4-7 membered heterocyclyl, C₃₋₇ cycloalkyl-4-7membered heterocyclyl, 4-7 membered heterocyclyl-C₃₋₇cycloalkyl orbi-(4-7 membered heterocyclyl).
 18. The compound of claim 1 wherein Q³is an unsubstituted or substituted, nitrogen-containing, 5-6 memberedheterocyclyl.
 19. The compound of claim 1 wherein Q³ is R³¹R³²N—. 20.The compound of claim 1 wherein: Q¹ is methyl; M is a moiety of theformula —CH₂R^(M), —CHOHR^(M), —C(═O)R^(M) or —C(═N—OH)R^(M); R^(M) isphenyl unsubstituted or substituted with F, Cl, Br, cyano, methoxy, C₁₋₃alkyl, CF₃, hydroxy, or nitro; A³ is oxygen or sulfur; L³ is selectedfrom (a) C₁₋₃ alkyl, which may be unsubstituted or substituted, andindependently may be unbranched or branched, and (b) C₄₋₅ alkyl, whichis branched or substituted, or both; and Q³ is R³¹R³²N—.
 21. Thecompound of claim 1 wherein: Q¹ is methyl; M is a moiety of the formula—CH₂R^(M), —CHOHR^(M) or —C(═O)R^(M); R^(M) is phenyl unsubstituted orsubstituted with F, Cl, Br, cyano, methoxy, C₁₋₃ alkyl, CF₃, hydroxy, ornitro; A³ is oxygen or sulfur; L³ is unsubstituted or substituted C₁₋₅alkyl or C₂₋₅ alkenyl, or L³ is absent; and Q³ is an unsubstituted orsubstituted, nitrogen-containing, 5-6 membered heterocyclyl.
 22. Acompound of claim 1 selected from the group consisting of:(2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanoneoxime;(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;[2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;(3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitro-phenyl)-methanone;(4-Bromophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Bromophenyl)-[2-(1-ethyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[3-methyl-2-(1-methyl-piperidin-4-ylsulfanyl)-3H-imidazol-4-yl]-methanone;(4-Bromophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-ylmethanone;4-{Hydroxy-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methyl}-benzonitrile;and(4-Bromophenyl)-[2-(1-sec-butyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 23. A compound of claim 1selected from the group consisting of:(2-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Bromophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-{3-methyl-2-[2-(1-methylpyrrolidin-2-yl)-ethylsulfanyl]-3H-imidazol-4-yl}-methanone;(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(3-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[3-methyl-2-(3-piperidin-1-yl-propylsulfanyl)-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone oxime;(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;[2-(3-Dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-phenyl-methanone;(3,5-Dichlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-trifluoromethyl-phenyl)-methanone;[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitrophenyl)-methanone;and(4-Bromophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 24. A compound of claim 1selected from the group consisting of:(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone;and[2-(1-Isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitrophenyl)-methanone;or a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 25. The compound of claim1 having the formula(4-Chlorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanoneor a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 26. The compound of claim1 having the formula(4-Fluorophenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanoneor a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 27. The compound of claim1 having the formula[2-(1-Isopropylpiperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-(4-nitro-phenyl)-methanoneor a pharmaceutically acceptable ester, ether, N-oxide, amide, salt,hydrate or isotopically labeled form thereof.
 28. A compound of claim 1of the formula (II):

wherein: Q¹ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl and C₂₋₇ alkenyl; wherein Q¹ may be substituted with one ormore substituents selected from the group consisting of halo, cyano,hydroxy, OR¹¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino(H₂N—), R¹¹HN—, R¹¹R²N—, amido (H₂NC(O)), R¹¹HNC(O), R¹¹R²NC(O) andR¹¹OC(O), and wherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅haloalkyl or C₂₋₅ alkenyl; R^(M) is selected from the group consistingof C₁₋₇ alkyl, R^(M1)HN—, R^(M1)R^(M2)N—, C₃₋₇ cycloalkyl, aryl, biaryland 4-7 membered heterocyclyl, wherein R^(M) may be substituted with oneor more substituents independently selected from the group consisting ofhalo, cyano, hydroxy, OR^(M1), C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl,nitro, amino (H₂N—), R^(M1)HN—, R^(M1)R^(M2)N—, amido (H₂NC(O)),R^(M1)HNC(O) and R^(M1)R^(M2)NC(O), and wherein R^(M1) and R^(M2) areindependently C₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; L³ is C₁₋₇alkyl or C₂₋₇ alkenyl; wherein L³ may be substituted with one or moresubstituents selected from the group consisting of halo, hydroxy,methoxy and amino (H₂N—); or L³ is absent; and Q⁴ is hydrogen; or aderivative thereof that bears one or more protecting groups.
 29. Acompound of claim 28, wherein Q¹ is unsubstituted C₁₋₃ alkyl.
 30. Acompound of claim 28, wherein Q¹ is methyl.
 31. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of claim 1, 20, 21, or
 24. 32. A Method of inhibiting histamineH₃ receptor activity in a subject, comprising administering an effectiveamount of a compound of claim 1, 21, or 24 to a subject in need of suchinhibition of histamine H₃ receptor activity.
 33. A method of treating asubject having a disease or condition modulated by histamine H₃ receptoractivity, comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 1, 21, or
 24. 34. A method ofclaim 33, wherein said disease or condition is selected from the groupconsisting of sleep/wake disorders, arousal/vigilance disorders,migraine, asthma, dementia, mild cognitive impairment (pre-dementia),Alzheimer's disease, epilepsy, narcolepsy, eating disorders, motionsickness, vertigo, attention deficit hyperactivity disorders, learningdisorders, memory retention disorders, schizophrenia, and upper airwayallergic response.
 35. A method for treating a disease or conditionmodulated by at least one receptor selected from the histamine H₁receptor and the histamine H₃ receptor, said method comprising (a)administering to a subject a histamine H₁ receptor antagonist compound,and (b) administering to the subject a compound of claim 1, said methodproviding a therapeutically effective amount of said compounds.
 36. Themethod of claim 35 wherein the histamine H₁ receptor antagonist and thecompound of claim 1 are present in the same dosage form.
 37. A methodfor treating diseases or conditions modulated by at least one receptorselected from the histamine H₂ receptor and the histamine H₃ receptor ina subject, comprising (a) administering to the subject a histamine H₂receptor antagonist compound, and (b) administering to the subject acompound of claim 1, said method providing a therapeutically effectiveamount of said compounds.
 38. The method of claim 37 wherein thehistamine H₂ receptor antagonist and the compound of claim 1 are presentin the same dosage form.
 39. A method for studying disorders mediated bythe histamine H₃ receptor, comprising using an ¹⁸F-labeled compound ofclaim 1 or 23 as a positron emission tomography molecular probe.
 40. Aprocess for the production of a compound of the formula (11):

wherein: Q¹ is selected from the group consisting of C₁₋₇ alkyl, C₁₋₇haloalkyl and C₂₋₇ alkenyl; wherein Q¹ may be substituted with one ormore substituents selected from the group consisting of halo, cyano,hydroxy, OR¹¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino(H₂N—), R¹¹HN—, R¹¹R¹²N—, amido (H₂NC(O)), R¹¹HNC(O), R¹¹R¹²NC(O) andROC(O), and wherein R¹¹ and R¹² are independently C₁₋₅ alkyl, C₁₋₅haloalkyl or C₂₋₅ alkenyl; R^(M) is selected from the group consistingof C₁₋₇ alkyl, R^(M1)HN—R^(M1)R^(M2)N—, C₃₋₇ cycloalkyl, aryl, biaryland 4-7 membered heterocyclyl, wherein R^(M) may be substituted with oneor more substituents independently selected from the group consisting ofhalo, cyano, hydroxy, OR^(M1), C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl,nitro, amino (H₂N—), R^(M1)HN—, R^(M1)R^(M2)N—, amido (H₂NC(O)),R^(M1)HNC(O) and R^(M1)R^(M2)NC(O), and wherein R^(M1) and R^(M2) areindependently C₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; A³ is NH, NR³,sulfur or oxygen, wherein R³ is C₁₋₅ alkyl; L³ is C₁₋₇ alkyl or C₂₋₇alkenyl; wherein L³ may be substituted with one or more substituentsselected from the group consisting of halo, hydroxy, methoxy and amino(H₂N—); or L³ is absent; and Q³ is selected from the group consisting ofC₁₋₇ alkyl, C₁₋₇ haloalkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₅₋₇cycloalkenyl, aryl, 4-7 membered heterocyclyl, C₃₋₇ cycloalkyl-4-7membered heterocyclyl, 4-7 membered heterocyclyl-C₃₋₇ cycloalkyl,bi-(4-7 membered heterocyclyl), R³¹HN—, R³¹R³²N—, azinoyl (R³¹HN⁺(O⁻) orR³¹R³²N⁺(O⁻)), C₃₋₇cycloalkylamino, 4-7 membered heterocyclylamino, arylC₁₋₆alkylamino, C₃₋₇cycloalkylsulfanyl, 4-7 mebered heterocyclylsulfanyland 4-7 membered heterocyclyloxy; wherein Q³ may be substituted with oneor more substituents selected from the group consisting of halo, cyano,hydroxy, OR³¹, C₁₋₅ alkyl, C₁₋₅ haloalkyl, C₂₋₅ alkenyl, nitro, amino(H₂N—), R³¹HN—, R³¹R³²N—, amido (H₂NC(O)), R³¹HNC(O), R³¹R³²NC(O),R³¹OC(O), C₃₋₇ cycloalkyl, monocyclic 4-7 membered heterocyclyl andmonocyclic 4-7 membered heterocyclyl-C₁₋₆ alkyl, and wherein R³¹ and R³²are independently C₁₋₅ alkyl, C₁₋₅ haloalkyl or C₂₋₅ alkenyl; thatcomprises treating a compound of the formula (5b)

wherein Q⁴ is hydrogen, with an oxidizing agent resulting in anintermediate compound of the formula (10)

and treating said intermediate compound (10) with a reagent H—A³—L³—Q³,wherein L³ of the reagent H—A³—L³—Q³ is independent of L³ of formula(5b) and formula (10), in the presence of a base in a suitable solventyielding said compound of formula II.
 41. A process according to claim40, wherein said oxidizing agent is either hydrogen peroxide in aceticacid, or 3-chloroperoxybenzoic acid in dichloromethane or diethyl ether.42. A process according to claim 40, wherein said base is an alkalimetal hydride.
 43. A process according to claim 42, wherein said alkalimetal hydride is sodium hydride.
 44. A process according to claim 40,wherein said suitable solvent is a member selected from the groupconsisting of dimethylformamide, benzene, 1,2-dimethoxyethane andtetrahydrofuran.
 45. A process according to claim 44, wherein saidsuitable solvent is tetrahydrofuran.